Embolic microspheres

Abstract

In some aspects, the present disclosure relates to injectable particles containing at least one pH modifier configured to be released from the injectable particles in vivo when the injectable particles are used to embolize an intratumoral artery of a tumor. In some cases, the pH modifier can be an alkaline agent having a pH of 7.5, a buffer having a pKa of 7.6 or greater, or both. Other aspects of the present disclosure relate to preloaded containers containing such injectable particles and methods of using such injectable particles.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of July 12, 2018, application number 201880046400.2, and invention name “Embolization Microspheres”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 531,956, filed on July 13, 2017, entitled “Embolic Microspheres,” the entire disclosure of which is incorporated herein by reference. Background Art

[0004] Many clinical manifestations benefit from modulation of the vascular, lymphatic, or ductal systems by restricting the flow of body fluids or secretions. For example, the technique of embolization involves the introduction of microparticles into the circulation to occlude blood vessels, for example to stop or prevent bleeding or to cut off blood flow to a structure or organ, as a means of limiting the delivery of essential oxygen and nutrients to the target tissue. Permanent or temporary occlusion of blood vessels is desirable for the management of a variety of diseases and conditions.

[0005] In a typical embolization procedure, local anesthesia is first administered over the common artery. The artery is then percutaneously punctured and a catheter is inserted. Fluoroscopy is used to guide the catheter to the area of ​​interest. Angiography is then performed by injecting a contrast agent through the catheter. Embolic particles are then deposited through the catheter. The embolic particles are selected based on, for example, the size of the vessel to be occluded, the desired duration of occlusion, and / or the type of disease or condition to be treated, among other factors. A subsequent angiogram is typically performed to confirm the specificity and completeness of the arterial occlusion.

[0006] Currently, various polymer-based microspheres are used for vascular embolization. Typically, these microspheres are guided to the predetermined embolization site via a microcatheter. Many commercially available embolic microspheres are made of polymers. Commonly used commercial materials for this purpose include polyvinyl alcohol (PVA), including acetalized PVA (e.g., Contour SE TM Embolic agents, Boston Scientific, Natick, MA, USA), and cross-linked acrylic acid hydrogels (e.g., Microspheres, embolic microspheres composed of triacrylic acid cross-linked with gelatin). Similar microspheres have been used for chemoembolization to increase the residence time of the therapeutic agent after delivery. In one specific case, the therapeutic agent (doxorubicin) has been added directly to polyvinyl alcohol hydrogel microspheres so that it can be released locally after delivery (e.g., DC Beads).TM Drug Delivery Chemoembolization System, Biocompatibles International plc, Farnham, Surrey, UK). Other examples of embolic microspheres include those sold under the trade names The scavenger was purchased from CeloNova BioSciences (San Antonio, TX). -F (poly [bis (trifluoroethoxy) phosphazene]) coated hydrogel core (eg, containing methyl methacrylate polymer); trade name Bead Block TM Embolic microspheres containing acrylamide-based PVA polymer were purchased from Biocompatibles International, Inc. (Oxford, CT); and Embolic microspheres containing PVA-sodium acrylate copolymer were purchased from Merit Medical Systems, Inc. (South Jordan, UT, USA). Other examples of commercially available microspheres include those containing embedded radioisotopes (e.g., 90 Y) glass microspheres, specifically TheraSpheres TM , MDS Nordion, Ottawa, Canada; and containing a chelating radioisotope ( 90 Y) monomer polymer microspheres, specifically SIRTex Medical, New South Wales, Australia.

[0007] Embolic microparticles have been used in transarterial embolization (TAE) and transarterial chemoembolization (TACE). The goal of TACE or TAE procedures is to controllably embolize the local tumor microenvironment, effectively starving tumor cells by removing upstream sources of oxygen and glucose. However, tumor progression is known to result in intratumoral lactic acidosis as a byproduct of the Warburg effect and high levels of hypoxia. It has been hypothesized that TACE or TAE can increase hypoxia and the inability to flush lactate out of the tumor, and ultimately this localization of high concentrations of lactic acidosis reduces the rate of glycolysis, thereby reducing the efficacy of TACE or TAE by converting cancer cells into a dormant state, by arresting cells in the G0 / G1 phase, and by reducing their dependence on glucose. See, for example, Chao et al., "A large non-randomized cohort and randomized study of local control of hepatocellular carcinoma by targeting intratumoral lactic acidosis." Elife.2016 Aug 2;5.Pii:e15691.Doi:10.7554 / eLife.15691. In other words, lactic acidosis, which is normally present in tumors and may be exacerbated by TAE or TACE treatment, effectively protects cancer cells from glucose starvation. It has been further hypothesized that this protective effect depends on the coexistence of lactate and hydrogen ions, and that removing either of these will abolish this effect. Ibid., see also Jiansheng Xie et al., "Beyond the Warburg effect - the dual metabolic nature of cancer cells," Scientific Reports, 4:Paper number:4927 (2014), DOI:10.1038 / srep04927 and Hao Wu et al., "The central role of lactic acidosis in the resistance of cancer cells to glucose deprivation-induced cell death," J Pathol. 2012 Jun;227(2):189-99. doi:10.1002 / path.3978. A recently developed surgical procedure has been shown to improve clinical outcomes in patients with liver cancer, with better cellular responses and patient survival observed. Chao et al., supra. During this surgical procedure, 5% sodium bicarbonate may alternatively be infused with doxorubicin-lipiodol emulsion and oxaliplatin / homocamptothecin, with the dose adjusted according to tumor size, followed by PVA ( The artery was permanently embolized using microspheres (microspheres) and microcoils (Tornado, COOK Medical, USA).

[0008] There is a continuing need in the art for improved injectable particles and therapeutic approaches using such particles to cause local modifications of the tumor microenvironment to enhance the efficacy of glucose and oxygen restriction therapies. Summary of the Invention

[0009] According to some aspects, the present disclosure relates to injectable particles comprising at least one pH modifier configured to be released from the injectable particles in vivo when the injectable particles are used to embolize an intratumoral artery of a tumor.

[0010] In various embodiments, the injectable particles can be spherical or non-spherical microparticles, and the diameter of the injectable particles can range from 20 micrometers (μm) or less to 5000 micrometers or more.

[0011] In various embodiments that can be used in conjunction with any of the foregoing aspects and embodiments, the injectable particles can be configured such that when an intratumoral artery of a tumor is embolized with the injectable particles, the injectable particles release a pH adjuster, thereby forming a microenvironment in the vascular bed of the tumor downstream of the injectable particles, the microenvironment having a higher pH than that which would exist in the absence of the pH adjuster (e.g., when embolized with injectable particles of the same composition except for the removal of the pH adjuster). This higher pH microenvironment can be maintained for at least 1 hour and up to 8 weeks or more, for example, within a range of 1 hour to 4 hours to 12 hours to 1 day to 2 days to 4 days to 1 week to 2 weeks to 4 weeks to 8 weeks (i.e., within a range between any two of the foregoing values), and in some cases, within a range of 2 weeks to 4 weeks.

[0012] In various embodiments that may be used in combination with any of the preceding aspects and embodiments, the pH adjusting agent can be an alkaline agent having a pH of 7.5 or above (e.g., the pH when dissolved in water at a concentration of 100 mM at 25° C.), and in some cases a pH in the range of 7.5 to 10.0.

[0013] In various embodiments that may be used in conjunction with any of the foregoing aspects and embodiments, the pH adjuster can be a pH adjuster having a pKa value of 7.6 or above, in some cases in the range of 7.6 to 35 (e.g., a pKa value extrapolated to infinite dilution in water at 25° C. (buffer concentration = 0), also referred to as a pKa value). 0 value) buffer.

[0014] In various embodiments that may be used in combination with any of the preceding aspects and embodiments, the pH adjuster can be an organic compound (e.g., organic amines, zwitterionic organic compounds, and many other organic compounds) or an inorganic compound (e.g., carbonates, phosphates, phosphazenes, and many other inorganic compounds).

[0015] In various embodiments that may be applied in combination with any of the preceding aspects and embodiments, the pH adjuster may be present in the injectable particles in an amount ranging from 10 wt% to 50 wt% based on the total weight of the injectable particles.

[0016] In various embodiments that may be used in combination with any of the preceding aspects and embodiments, the pH adjuster can be released from the injectable particles by a mechanism selected from (a) diffusion from all or a portion of the injectable particles, (b) biodegradation of all or a portion of the injectable particles, or (c) a combination of (a) and (b).

[0017] In various embodiments that may be employed in conjunction with any of the foregoing aspects and embodiments, the injectable particles can include a biostable core and a coating comprising a pH adjuster. The biostable core can be, for example, a hydrogel core. The biostable core can, for example, comprise one or more methyl methacrylate monomers and vinyl alcohol monomers. In addition to the pH adjuster, the coating can further comprise additional materials (such as a binder material or a matrix material). In some cases, the injectable particles can further comprise an additional coating comprising poly[bis(trifluoroethoxy)phosphazene].

[0018] In various embodiments that may be used in combination with any of the preceding aspects and embodiments, the injectable particles may further comprise at least one therapeutic agent.

[0019] In various embodiments that may be used in combination with any of the preceding aspects and embodiments, the injectable particles may further comprise at least one osmotic pressure agent.

[0020] In other aspects of the present disclosure, the injectable particles according to any of the foregoing aspects and embodiments may be provided in a container. In certain embodiments, the container may be a container configured to be connected to a delivery catheter (eg, a syringe and other suitable containers).

[0021] In other aspects, the present disclosure relates to a method of embolization, comprising administering an injectable particle according to any of the foregoing aspects and embodiments into an intratumoral artery of a tumor. Upon administration, a pH modifier is released from the injectable particle, thereby forming a microenvironment with an elevated pH in the vascular bed of the tumor downstream of the injectable particle. For example, the pH of the microenvironment can be higher than the pH that would exist in the absence of the pH modifier (e.g., when administering injectable particles of the same composition except for the removal of the pH modifier).

[0022] In various embodiments, the pH adjuster is released for a period of at least one hour after administration of the injectable particles, for example, for a period of time in the range of 1 hour to 12 hours to 1 day to 2 days to 4 days to 1 week to 2 weeks to 4 weeks to 8 weeks (i.e., in a range between any two of the foregoing values) after administration of the injectable particles, and in some cases for a period of time in the range of 2 to 4 weeks after administration of the injectable particles.

[0023] In various embodiments, the pH adjusting agent is released in a manner that maintains the pH of the microenvironment above the pH that would exist in the absence of the pH adjusting agent (e.g., the pH that would exist in the microenvironment upon administration of injectable particles of the same composition except for the removal of the pH adjusting agent) for a period of at least one hour after administration of the injectable particles, for example, within a range of 1 hour to 4 hours to 12 hours to 1 day to 2 days to 4 days to 1 week to 2 weeks to 4 weeks to 8 weeks (i.e., within a range between any two of the foregoing values) after administration of the injectable particles, and in some cases, within a range of 2 to 4 weeks after administration of the injectable particles.

[0024] This application also covers the following projects:

[0025] 1. An injectable particle comprising at least one pH adjusting agent configured to be released from the injectable particle in vivo when the injectable particle is used to embolize an intratumoral artery of a tumor.

[0026] 2. The injectable particle according to claim 1, wherein the injectable particle is configured such that when the injectable particle is used to embolize an intratumoral artery of a tumor, the injectable particle releases the pH adjuster to form a microenvironment in the vascular bed of the tumor located downstream of the injectable particle, wherein the microenvironment has a pH higher than that which would exist in the absence of the pH adjuster.

[0027] 3. The injectable particle according to any one of items 1 to 2, wherein the pH adjuster is (a) an alkaline agent having a pH value of 7.5 or higher, (b) a buffer having a pKa value of 7.6 or higher, or a combination of (a) and (b).

[0028] 4. The injectable particle according to any one of items 1 to 2, wherein the pH adjuster is (a) an alkaline agent having a pH value in the range of 7.5 to 10, (b) a buffer having a pKa value in the range of 8 to 35, or (c) a combination of (a) and (b).

[0029] 5. The injectable particle according to any one of items 1 to 4, wherein the pH adjuster is selected from organic amines, zwitterionic organic compounds, and phosphazenes.

[0030] 6. The injectable particle according to any one of items 1 to 5, wherein the pH adjuster is present in the injectable particle in an amount ranging from 10 wt% to 50 wt% based on the total weight of the injectable particle.

[0031] 7. The injectable particle according to any one of items 1 to 6, wherein the pH adjuster is released from the injectable particle by a mechanism selected from: (a) diffusion from all or a portion of the injectable particle, (b) biodegradation of all or a portion of the injectable particle, or (c) a combination of (a) and (b).

[0032] 8. The injectable particle according to any one of items 1 to 7, wherein the injectable particle comprises a biostable core and a coating comprising the pH adjuster.

[0033] 9. The injectable particle according to item 8, wherein the biostable core is a hydrogel core.

[0034] 10. The injectable particle according to any one of items 8 to 9, wherein the biostable core comprises a polymer comprising one or more of a methyl methacrylate monomer and a vinyl alcohol monomer.

[0035] 11. The injectable particle according to any one of items 8 to 10, wherein the injectable particle further comprises an additional coating comprising poly[bis(trifluoroethoxy)phosphazene].

[0036] 12. The injectable particle according to any one of items 8 to 11, wherein the coating further comprises a binder material or a matrix material.

[0037] 13. The injectable particle according to any one of items 1 to 12, wherein the injectable particle further comprises at least one therapeutic agent.

[0038] 14. The injectable particle according to any one of items 1 to 13, wherein the injectable particle further comprises at least one osmotic pressure agent.

[0039] 15. A container configured to be attached to a delivery catheter and preloaded with injectable particles according to any one of items 1 to 14.

[0040] Details of various aspects and embodiments of the invention are set forth in the following description. Other features and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION

[0041] The present disclosure relates to injectable particles comprising at least one pH adjusting agent that is released at a site of action in vivo.

[0042] In certain embodiments, the injectable particles are configured to release at least one pH adjusting agent in an amount sufficient to temporarily maintain the microenvironment associated with the injectable particles at a pH that is higher than the pH that would exist in the absence of the injectable particles.

[0043] In certain embodiments, the injectable particles are designed such that, when intratumoral arteries of a tumor are embolized with the injectable particles, the injectable particles release at least one pH adjusting agent in such a manner that a microenvironment is formed in the vascular bed of the tumor downstream of the injectable particles. In various embodiments, the microenvironment has a pH that is higher (e.g., at least 0.2 pH units higher, preferably at least 0.5 pH units higher) than the pH that would exist in the microenvironment in the absence of the pH adjusting agent (e.g., higher than the pH of the microenvironment formed in the vascular bed of the tumor downstream of the injectable particles when embolization is performed with injectable particles of the same composition except for the pH adjusting agent). In certain of these embodiments, the injectable particles are configured to release the pH adjusting agent in an amount sufficient to maintain the pH of the microenvironment above the pH that would exist in the microenvironment in the absence of the pH adjusting agent for at least 1 hour up to 8 weeks or more, for example, for a period of time in the range of 1 hour to 4 hours to 12 hours to 1 day to 2 days to 4 days to 1 week to 2 weeks to 4 weeks to 8 weeks (i.e., in a range between any two of the foregoing values), and in some cases, in the range of 2 to 4 weeks.

[0044] The injectable particles disclosed herein can be used to treat a variety of diseases and conditions in a variety of subjects. Subjects include vertebrate subjects, particularly humans and various warm-blooded animals (including pets and livestock). As used herein, "treat" refers to the prevention of a disease or condition, the alleviation or elimination of symptoms associated with a disease or condition, or the significant or complete elimination of a disease or condition. Preferred treatments include embolization therapy.

[0045] In certain embodiments, the injectable particles disclosed herein can be used in TACE or TAE treatments. Because the injectable particles disclosed herein contain a pH modifier that is released in vivo, such microparticles can be used in TACE and TAE procedures in which the injectable particles are used to embolize the tumor microenvironment while simultaneously providing controlled regulation of the intratumoral pH through the release of the pH modifier in vivo. Without wishing to be bound by theory, it is hypothesized that controlled regulation of the intratumoral pH to an alkaline pH will reduce or eliminate lactic acidosis, leading to higher glucose dependency and, therefore, increased tumor cell death, resulting in more effective TACE and TAE treatments.

[0046] The pH adjusting agents used in the present disclosure include a wide variety of organic and inorganic pH adjusting agents. In various embodiments, the pH adjusting agents used include (a) a pH adjusting agent having a pH value (e.g., a pH value at 100 mM concentration in water at 25°C) greater than 7.4, typically in the range of 7.5 to 10 (e.g., a pH value in the range of 7.5 to 8.0 to 8.5 to 9.0 to 9.5 to 10) (this means that the selected pH range can be within the range between any two of the aforementioned values); (b) a pH adjusting agent having a pKa value (e.g., extrapolated to infinite dilution in water (buffer concentration = 0) at 25°C, also referred to as a pKa value) greater than 7.4, typically in the range of 7.5 to 10 (e.g., a pH value in the range of 7.5 to 8.0 to 8.5 to 9.0 to 9.5 to 10); 0 (a) a buffering agent having at least one pKa value (which means that the selected pKa range can be in the range between any two of the aforementioned values) greater than 7.6, typically in the range of 7.6 to 35 (e.g., having a pKa value in the range of 7.6 to 8.0 to 8.5 to 9.0 to 9.5 to 10 to 11 to 12 to 13 to 14 to 16 to 18 to 20 to 25 to 30 to 35); and (c) a pH adjusting agent having both the pH value of (a) and the pKa value of (b).

[0047] Specific examples of inorganic pH adjusters include carbonates such as sodium carbonate (pH 10.5, 25°C, 100 mM dissolved in H2O), potassium carbonate (pH 10.5, 25°C, 100 mM dissolved in H2O), and calcium carbonate (pH 9.9, 25°C, 100 mM dissolved in H2O); and bicarbonates (also known as hydrogen carbonates) such as sodium hydrogen carbonate (pH 8.3, 25°C, 100 mM dissolved in H2O) and potassium hydrogen carbonate (pH 8.3, 25°C, 100 mM dissolved in H2O). Carbonates act as buffers and have two pKa values: one for the reaction of bicarbonate with carbonic acid and the other for the reaction of bicarbonate with carbonate. For sodium bicarbonate, the pKa for the bicarbonate <-> carbonic acid reaction is -6.4, and the pKa for the bicarbonate <-> carbonate reaction is -10.3.

[0048] Examples of inorganic pH adjusters also include phosphates, including dibasic phosphates such as disodium hydrogen phosphate (pH ~8.7-9.3, 25°C, 50 mg / mL dissolved in H2O) or dipotassium hydrogen phosphate (pH ~8.7-9.3, 25°C, 1 M dissolved in H2O). Phosphates act as buffers and have three pKa values: one for phosphoric acid <-> monobase reactions, one for monobase <-> dibase reactions, and one for dibase <-> tribase reactions. For sodium phosphate, the pKa for phosphoric acid <-> monobase reactions is ~2.12, the pKa for monobase <-> dibase reactions is ~7.21, and the pKa for dibase <-> tribase reactions is ~12.67.

[0049] Other examples of inorganic pH adjusters include phosphazenes.

[0050] A variety of organic pH adjusters can be used in the present disclosure. In certain embodiments, one or more inorganic buffers are selected for use in the injectable particles. Suitable inorganic buffers can be selected, for example, from one or more of the following buffers, many of which are zwitterionic (each buffer is listed along with its reported pKa value at 25°C): DIPSO (N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid) (7.6), TAPSO (2-hydroxy-3-[tris(hydroxymethyl)methylamino]-1-propanesulfonic acid) (7.6), triethanolamine (7.8), N-ethylmorpholine (7.8), POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid) ))(7.8), HEPPSO(N-(2-hydroxyethyl)piperazine-N-(2-hydroxypropanesulfonic acid))(7.9), HEPPS(4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid)(8.0), Tricine(N-[tris(hydroxymethyl)methyl]glycine)(8.1), Tris(tris(hydroxymethyl)aminomethane)(8.1), glycineamide(8.1), glycylglycine(8.3), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid))(8. 3), bicine (N,N-bis(2-hydroxyethyl)glycine) (8.3), TAPS (N-[tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid) (8.4), morpholine (8.5), N-methyldiethanolamine (8.5), AMPD (2-amino-2-methyl-1,3-propanediol) (8.8), diethanolamine (8.8), AMPSO (N-(1,1-dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid) (9.1), CHES (2-(cyclohexyl)

[0015] The present invention also includes but is not limited to the following: 1,2-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.3), 1,3-diaminopropane (10.4 ...

[0051] The aforementioned compounds are generally also alkaline agents.

[0052] As previously stated, the present disclosure relates to injectable particles that release one or more pH modifiers (eg, selected from the above, etc.) in vivo.

[0053] The pH adjusting agent may be released by any suitable mechanism, including (a) by diffusion from all or a portion of the injectable particles (e.g., wherein all or a portion of the injectable particles correspond to a matrix containing the pH adjusting agent and from which the pH adjusting agent diffuses); (b) by biodegradation (e.g., by dissolution and / or biodegradation) of all or a portion of the injectable particles (e.g., wherein all or a portion of the injectable particles (i) contain the pH adjusting agent and (ii) dissolve and / or biodegrade in vivo to release the pH adjusting agent); or a combination of the foregoing; and other suitable mechanisms.

[0054] Typically, one or more pH adjusters are present in the injectable particles in an amount ranging from 1% to 90%, more typically from 10% to 50% by weight, based on the total weight of the injectable particles.

[0055] The shape of the injectable particles of the present disclosure can vary widely. In certain embodiments, they are spherical (have a spherical shape).

[0056] The particle size of the injectable particles of the present disclosure can vary significantly, with typical diameters ranging from, for example, 25 micrometers (μm) or less to 5000 micrometers or more, for example, within the range of 25 μm to 50 μm to 75 μm to 100 μm to 150 μm to 250 μm to 500 μm to 750 μm to 1000 μm to 1500 μm to 2000 μm to 2500 μm to 5000 μm (i.e., including all ranges spanning any two of the aforementioned values). Where aggregates of injectable particles are used, at least 95% by volume of the particles may fall within these ranges.

[0057] The injectable particles of the present disclosure can be biostable, biodegradable (e.g., dissolve and / or biodegrade in vivo), or partially biostable and partially biodegradable (e.g., where the injectable particle comprises a biostable core and a coating that dissolves and / or biodegrades in vivo). As used herein, a microparticle, or a portion thereof, is "biodegradable" if it loses quantifiable mass. This process can occur over a period of hours to days to weeks to months to years. The degradation mechanism can be due to loss of mass or molecular weight. As used herein, a microparticle, or a portion thereof, is "biostable" if it is not "biodegradable." In some cases, the microparticle, or a portion thereof, is "biostable" if it remains present in the vasculature for at least 1 year, preferably at least 5 years.

[0058] The injectable particles according to the present disclosure and portions thereof (e.g., core, coating, etc.) can be constructed using a variety of inorganic materials (e.g., glass, ceramic, metal, etc.), organic materials (e.g., non-polymeric organic compounds, polymers, etc.), and combinations of inorganic and organic materials.

[0059] In various advantageous embodiments, the injectable particles according to the present disclosure and portions thereof (e.g., core, coating, etc.) can be constructed using various polymers that can be biostable or biodegradable. Biodegradable polymers include polymers that biodegrade in vivo and dissolve in vivo. As used herein, a "biodegradable polymer" is a polymer that undergoes chain cleavage in vivo.

[0060] The injectable particles of the present invention may be non-crosslinked, or they may be covalently crosslinked and / or non-covalently crosslinked. Thus, in some embodiments, a crosslinking agent (e.g., a covalent crosslinking agent or an ionic crosslinking agent) may be present in the injectable particles, while in other embodiments, the crosslinking agent is not present in these particles.

[0061] Suitable organic materials for forming the injectable particles and parts thereof (e.g., core, coating, etc.) may be selected, for example, from one or more of the following materials, many of which are polymers: polyphosphazines, including poly[bis(trifluoroethoxy)phosphazene] and poly[bis(ethylalanyl)phosphazene]; vinyl monomer homopolymers and copolymers, including acetalizable vinyl alcohol homopolymers and copolymers (e.g., copolymers of vinyl alcohol with acrylic acid and its salts, copolymers of vinyl alcohol with 2-acrylamido-2-methylpropanesulfonic acid and its salts, etc.), polyvinyl ketone, polyvinyl carbazole, polyvinyl esters (e.g., polyvinyl acetate), polyvinyl halides (e.g., polyvinyl chloride), ethylene-vinyl acetate copolymers (EVA), polyvinylidene chloride, polyvinyl ethers (e.g., polyvinyl methyl ether), polyvinyl pyrrolidone, vinyl aromatics (e.g., polystyrenes, styrene-maleic anhydride copolymers), vinyl aromatic-olefin copolymers, including styrene-butadiene copolymers, styrene-ethylene-butylene copolymers (e.g., polystyrene-polyethylene / butylene-polystyrene (SEBS) copolymers, sold under the trade name G series polymers available commercially), styrene-isoprene copolymers (e.g., polystyrene-polyisoprene-polystyrene), acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrene copolymers, styrene-butadiene copolymers, and styrene-isobutylene copolymers (e.g., polyisobutylene-polystyrene and polystyrene-polyisobutylene-polystyrene block copolymers, as disclosed in U.S. Pat. No. 6,545,097 to Pinchuk); siloxane polymers and copolymers; polycarboxylic acid polymers and copolymers, including homopolymers and copolymers of polyacrylic acid and polymethacrylic acid, and their salts, ethylene-methacrylic acid copolymers, and ethylene- Acrylic acid copolymers in which some of the acid groups can be neutralized with zinc or sodium ions (commonly referred to as ionomers); polymers and copolymers of acrylates and methacrylates (e.g., copolymers of methyl methacrylate and triethylene glycol dimethacrylate); acetal polymers and copolymers; ketal polymers and copolymers (e.g., poly(1,4-phenylpropiophenone dimethylene ketal), poly(cyclohexane-1,4-diylacetone dimethylene ketone, etc.); polyimides; polyhydrazones; cellulosic polymers and copolymers, including cellulose acetate, cellulose nitrate, cellulose propionate, cellulose acetate butyrate, cellophane, rayon, triacetate rayon, and cellulose acetate. Cellulose ethers (such as carboxymethyl cellulose and hydroxyalkyl cellulose); polyoxymethylene polymers and copolymers; polyimide polymers and copolymers (such as polyether block amides, polyamide imides, polyester imide imides, and polyether imides; polyamide polymers and copolymers, including nylon 6,6, nylon 12, polycaprolactam, polyacrylamide and polyether block amides; polysulfone polymers and copolymers, including polyarylsulfone and polyethersulfone; resins, including alkyd resins, phenolic resins, urea resins, melamine resins, epoxy resins, allyl resins and epoxy resins; polycarbonates; polyacrylonitrile; polybenzimidazole; polyesters, including polyethylene terephthalate and aliphatic polyester polyols. compounds, and copolymers of α-hydroxy acids such as polylactic acid (including dextrorotatory, levorotatory and meso forms), polyglycolide and polylactide, ε-caprolactone, polylactide-caprolactone, polyhydroxybutyrate, polyhydroxyvalerate, poly(p-dioxanone), polymers of cyclopropane carbonate (and its alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and 6,6-dimethyl-1,4-dioxan-2-one; polyether polymers and copolymers, including polyaryletherethers (such as polyphenylene oxide), polyetherketone, polyetheretherketone, and polyalkyloxides (such as polyethylene oxide (PEO) and polypropylene oxide); polythioethers; polyisocyanates;Polyolefin polymers and copolymers, including polyolefins such as polypropylene, polyethylene (low and high density, low and high molecular weight), polybutenes (such as polybut-1-ene and polyisobutylene), polyolefin elastomers (e.g., Santoprene), ethylene-propylene diene monomer (EPDM) rubbers, poly-4-methyl-pent-1-ene, ethylene-α-olefin copolymers, ethylene-methyl methacrylate copolymers, and ethylene-vinyl acetate copolymers; fluorinated polymers and copolymers, including polytetrafluoroethylenes (PTFE), tetrafluoroethylene-hexafluoropropylene copolymers (FEP), modified ethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidene fluoride (PVDF); thermoplastic polyurethanes (TPU); elastomers, such as polyurethane elastomers; Polymers, and polyurethane copolymers (including block and random copolymers based on polyether, polyester, polycarbonate, polyisobutylene, aliphatic hydrocarbon, aromatic hydrocarbon and mixtures thereof; polyparaxylene polymers; polyiminocarbonates; (polyether-polyester) copolymers, such as polyethylene oxide-polylactic acid copolymers; polyalkylene oxalates; polyoxoamides and polyoxoesters (including those containing amino and / or amide groups); polyorthoacids; waxes, such as paraffin; biopolymers, such as polypeptides, proteins, polysaccharides and fatty acids (and their esters), including gelatin, starch, collagen, polysaccharide anhydrides, fibrin, fibrinogen, elastin, alginic acid, chitosan, glycosaminoglycans (such as hyaluronic acid), and mixtures thereof.

[0062] In certain embodiments in which a biodegradable polymer is used, it is desirable to use a biodegradable polymer having non-acidic degradation products. Examples of biodegradable polymers reported to have non-acidic degradation products include polyacetals, polyketals (e.g., poly(1,4-phenylpropiophenone dimethylene ketal), poly(cyclohexane-1,4-diylacetone dimethylene ketone, etc.), polyphosphazenes (e.g., poly[bis(ethylalanyl)phosphazene], etc.), polyimides, polyhydrazones, and polyorthoesters, etc.

[0063] In certain embodiments, the injectable particles may include one or more coatings surrounding the core, at least one of which contains a pH adjuster. Such a coating containing a pH adjuster may consist essentially of the pH adjuster (e.g., may contain at least 90% by weight, at least 95% by weight, or at least 99% by weight of the pH adjuster), or may contain the pH adjuster in admixture with one or more other materials, such as a binder material and a matrix material, which may be selected from, for example, small molecule inorganic compounds, biostable polymers, and biodegradable polymers.

[0064] In some embodiments, known injectable particles can be coated with a coating containing one or more pH modifiers. Examples of such injectable particles include various polymer-based microspheres used for embolization of blood vessels. Specific examples include vinyl alcohol-based microspheres, including acetalized polyvinyl alcohol microspheres (e.g., Contour SE TM ), microspheres formed from copolymers of vinyl alcohol and acrylic acid and its salts (e.g., ), microspheres composed of copolymers of vinyl alcohol and 2-acrylamido-2-methylpropanesulfonic acid and its salts (for example, Bead Block TM ), microspheres composed of triacrylate cross-linked with gelatin (e.g., ), and microspheres comprising a hydrogel core comprising methyl methacrylate coated with poly[bis(trifluoroethoxy)phosphazene] (e.g., )wait.

[0065] In some embodiments, the injectable particles of the present disclosure include an osmotic agent. This osmotic agent can be added to increase the osmotic pressure in the hydration layer associated with the microparticles, which can increase the release of the pH adjuster from the microparticles, thereby improving the penetration of the pH adjuster, including the buffer, into tumor tissue. If present, the injectable particles can include an osmotic agent in an amount ranging from 5% to 40% based on the total weight of the injectable particles.

[0066] Examples of osmotic agents include: inorganic salts, such as sodium chloride, potassium chloride, sodium phosphate and potassium phosphate; and organic osmotic agents, including sugars (such as fructose, sucrose, dextrose and lactose); sugar alcohols (such as ethylene glycol, xylitol, sorbitol and mannitol); amino acids (such as L-arginine); and combinations thereof.

[0067] In some embodiments, the injectable particles of the present disclosure may include one or more therapeutic agents. If present, the injectable particles may include the therapeutic agent in an amount ranging from 0.0001% to 25% (e.g., in an amount ranging from 0.0001% to 0.001% to 0.01% to 0.1% to 1% to 5% to 10% to 15% to 20% to 25%) based on the total weight of the injectable particle (meaning that the selected amount can be within a range between any two of the stated values).

[0068] Examples of therapeutic agents that can be used in the embolic compositions of the present invention include toxins (e.g., ricin, radioisotopes, or any other drug capable of killing undesirable cells that make up cancer and other tumors (e.g., uterine fibroids)) and drugs that prevent the growth of undesirable cells.

[0069] Specific examples of therapeutic agents may be selected from suitable members of the following: antitumor agents / antiproliferative agents / antimitotic agents, including antimetabolites such as folic acid analogs / antagonists (e.g., methotrexate, etc.), purine analogs (e.g., 6-mercaptopurine, thioguanine, cladrin (which is a chlorinated purine nucleoside analog), etc.) and pyrimidine analogs (e.g., cytarabine, fluorouracil, etc.); alkaloids including taxanes (e.g., paclitaxel, docetaxel, etc.); alkylating agents such as alkyl sulfonates, Nitrogen mustards (e.g., cyclophosphamide, ifosfamide, etc.), nitrosoureas, ethyleneimines and methylmelamines, other alkylating agents (e.g., dacarbazine, etc.), antibiotics and analogs (e.g., daunorubicin, doxorubicin, idarubicin, mitomycin, bleomycin, plicamycin, etc.), platinum complexes (e.g., cisplatin, carboplatin, etc.), antitumor enzymes (e.g., asparaginase, etc.), drugs that affect microtubule dynamics (e.g., vinblastine, vincristine, colchicine, Epo D, epothilones), caspase activators, proteasome inhibitors, angiogenesis inhibitors (e.g., statins such as endostatin, cerivastatin and angiostatin, squalamine, etc.), rapamycin (sirolimus) and its analogs (e.g., everolimus, tacrolimus, zotarolimus, etc.), etoposide, and many other drugs (e.g., hydroxyurea, flavopiridol, procarbazine, mitoxantrone, camptothecin, etc.), various pharmaceutically acceptable salts and derivatives of the foregoing (e.g., esters, etc.), and combinations of the foregoing, and other agents. Other examples of therapeutic agents include radioisotopes including 90 Y. 32 P. 18 F. 140 La, 153 Sm, 165 Dy, 166 Ho, 169 Second, 169 Yb, 177 Lu, 186 Re、 188 Re、 103 Pd, 198 Au, 192 Ir, 90 Sr. 111 In or 67 Ga, as well as biologics, such as immunotherapeutic antibodies or other biological components.

[0070] In some embodiments, the injectable particles of the present disclosure contain a substance that increases the radiopacity of the particles (i.e., makes the polymer more absorptive to X-rays and therefore visible under X-ray imaging techniques such as X-ray fluoroscopy). Examples of radiopaque agents include metals, metal salts and metal oxides, and iodinated compounds. More specific examples of such radiopaque agents include gold, tungsten, platinum, tantalum, iridium, or other dense metals, barium sulfate, bismuth subcarbonate, bismuth trioxide, bismuth oxychloride, mepanematide, iopamidol, iothalamate sodium, sodium iodamide, and meglumine. If present, the injectable particles may contain a radiopaque agent in an amount ranging from 0.01% to 40% based on the total weight of the injectable particles.

[0071] The injectable particle compositions according to the present disclosure can be stored and transported in a sterile, dried form. The dried composition can be transported in, for example, a catheter, syringe, glass vial, ampoule, or other container (e.g., any container configured to interact with a delivery catheter), and can be mixed with a suitable liquid carrier (e.g., sterile water for injection, physiological saline, phosphate buffered saline, a solution containing an imaging contrast agent, etc.) before administration. Thus, the concentration of the composition to be injected can be freely varied by the surgeon in charge of the procedure, depending on the specific use being performed. One or more containers of liquid carrier can also be provided and transported in a kit together with the dry particles.

[0072] In other embodiments, the injectable particles can be stored in a sterile suspension comprising water and the injectable particles. As described above, the suspension can be stored in, for example, a catheter, syringe, glass vial, ampoule, or other container. The suspension can also be mixed with a suitable liquid carrier (e.g., sterile water for injection, physiological saline, phosphate buffered saline, a solution containing a contrast agent, etc.) before administration, thereby allowing the concentration of the administered microparticles in the suspension to be reduced before injection, if so desired by the operating physician. One or more containers of the liquid carrier can also be provided to form a kit.

[0073] The present invention encompasses various methods of administering the injectable particles of the present invention to achieve embolization or another procedure that would benefit from the injectable particles of the present invention. One skilled in the art can determine the most ideal method for administering the microparticles based on the type of treatment and the patient's condition, among other factors. Methods of administration include, for example, transdermal methods and other effective routes of administration. For example, the particle compositions of the present invention can be delivered via syringe or via a catheter (e.g., a microcatheter), which can be routed over a guidewire, a steerable microcatheter, a flow-directing microcatheter, or other devices.

[0074] Example 1

[0075] The coating material of the pH regulator is sprayed on the surface of the embolic microspheres to provide microspheres with a slow release of the pH regulator. In one embodiment, diethanolamine is dissolved in isopropyl alcohol and sprayed on the surface of the microspheres. The surface of the embolic microspheres is coated with diethanolamine so that the diethanolamine is present on the microspheres in an amount ranging from 10 wt% to 50 wt% based on the total weight of the coated microspheres. The microspheres can then be dried in a vacuum oven to remove excess solvent. If necessary, the microspheres can be diluted with a suitable solution (e.g., saline solution or contrast solution) to a dilution (volume) of 2-fold, 5-fold, 10-fold, 20-fold, or more, or can be subsequently diluted with a suitable solution (e.g., saline solution or contrast solution) before administration to a patient.

[0076] Example 2

[0077] Microparticles were formed as described in Example 1 except that an osmotic agent (specifically D-glucose) was added to the coating solution such that the osmotic agent was present on the microspheres in an amount ranging from 0.001 wt % to 5 wt % based on the total weight of the coated microspheres.

Claims

1. An injectable particle comprising: biostable core; and A coating comprising at least one pH adjuster configured to be released from the injectable particle in vivo when the injectable particle is used to embolize an intratumoral artery of a tumor, wherein the pH adjuster is a buffer having a pKa value of 7.6 or greater, wherein the pH adjuster is an organic compound.

2. The injectable particle of claim 1 , wherein the injectable particle is configured such that when an intratumoral artery of a tumor is embolized with the injectable particle, the injectable particle releases the pH adjuster to thereby form a microenvironment in the vascular bed of the tumor downstream of the injectable particle, the microenvironment having a pH higher than that which would exist in the absence of the pH adjuster. The injectable particle of claim 1 , wherein the injectable particle is a spherical or non-spherical particle.

4. The injectable particle of claim 1, wherein the injectable particle has a diameter in the range of 20 to 1500 microns. The injectable particle of claim 1 , wherein the pKa value is in the range of 7.6 to 35. 6 . The injectable particle of claim 1 , wherein the pH adjuster is present in the injectable particle in an amount ranging from 10 wt % to 50 wt % based on the total weight of the injectable particle.

7. The injectable particle of claim 1, wherein the pH adjuster is released from the injectable particle by a mechanism selected from the group consisting of: (a) diffusion from all or a portion of the injectable particle, (b) biodegradation of all or a portion of the injectable particle, or (c) a combination of (a) and (b).

8. The injectable particle of claim 1, wherein the biostable core is a hydrogel core.

9. The injectable particle of claim 1, wherein the biostable core comprises a polymer comprising one or more of a methyl methacrylate monomer and a vinyl alcohol monomer.

10. The injectable particle of claim 1, wherein the injectable particle further comprises an additional coating comprising poly[bis(trifluoroethoxy)phosphazene].

11. The injectable particle of claim 1, wherein the coating further comprises a binder material or a matrix material.

12. The injectable particle of claim 1, wherein the injectable particle further comprises at least one therapeutic agent.

13. The injectable particle of claim 1, wherein the injectable particle further comprises at least one osmotic pressure agent in an amount ranging from 5% to 40% based on the total weight of the injectable particle.

14. A container configured to be attached to a delivery catheter and preloaded with injectable particles comprising at least one pH adjuster, the pH adjuster configured to be released from the injectable particles in vivo when the injectable particles are used to embolize an intratumoral artery of a tumor, wherein the pH adjuster is an organic compound; the injectable particles comprising a biostable core; and a coating comprising at least one pH adjuster.

15. Use of injectable particles comprising at least one pH adjusting agent for preparing an embolic agent for administration into an intratumoral artery of a tumor, wherein the pH adjusting agent is an organic compound; the injectable particles comprise a biostable core; and a coating comprising at least one pH adjusting agent, the pH adjusting agent being configured to be released from the injectable particles in vivo when the injectable particles are used to embolize the intratumoral artery of a tumor.

16. The use of claim 15, wherein the injectable particle releases the pH adjuster in vivo to form a microenvironment in the vascular bed of a tumor located downstream from the injectable particle, wherein the microenvironment has a pH higher than that which would exist in the absence of the pH adjuster.

17. A kit comprising: The injectable particles of claim 1 in a container; and A liquid carrier is configured to be mixed with the injectable particles prior to administration.

18. A kit comprising a container and the injectable particles of claim 1 stored in a sterile suspension contained in the container.