阅读说明：本技术 栓塞微球 (Embolic microspheres ) 是由 曾红霞 布鲁斯·R·福赛思 曹宏 马修·R·德威特 海蒂·施万兹 于 2018-07-12 设计创作，主要内容包括：在一些方面,本公开是关于可注射粒子,这些可注射粒子含有构造成在用可注射粒子将肿瘤的肿瘤内动脉栓塞时在体内从可注射粒子中释放的至少一种pH调节剂。某些情况下,pH调节剂可以是具有7.5的pH值的碱性剂、具有7.6或以上的pKa值的缓冲剂、或两者。本公开的其他方面是关于容纳这种可注射粒子的预加载容器、及使用这种可注射粒子的方法。(In some aspects, the present disclosure is directed to injectable particles containing at least one pH modifying agent configured to be released from the injectable particles in vivo upon embolization of an intratumoral artery of a tumor with the injectable particles. In some cases, the pH adjusting agent can be an alkaline agent having a pH of 7.5, a buffer having a pKa of 7.6 or more, or both. Other aspects of the disclosure are directed to preloaded containers containing such injectable particles, and methods of using such injectable particles.)

1. An injectable particle comprising at least one pH adjusting agent configured to be released from the injectable particle in vivo upon embolization of an intratumoral artery of a tumor with the injectable particle.

2. The injectable particle of claim 1, wherein the injectable particle is configured such that upon embolization of an intratumoral artery of a tumor with the injectable particle, the injectable particle releases the pH-modifying agent to form a microenvironment in the vascular bed of the tumor at a location downstream of the injectable particle having a pH higher than would be present in the absence of the pH-modifying agent.

3. The injectable particle according to any one of claims 1 to 2, wherein the pH adjusting agent is (a) an alkaline agent having a pH value of 7.5 or more, (b) a buffer having a pKa value of 7.6 or more, or a combination of (a) and (b).

4. The injectable particle of any one of claims 1 to 2, wherein the pH adjusting agent 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).

5. The injectable particle according to any one of claims 1 to 4, wherein the pH modifier is selected from organic amines, zwitterionic organic compounds, and phosphazenes.

6. The injectable particle of any one of claims 1 to 5, wherein the pH adjusting agent is present in the injectable particle in an amount ranging from 10 to 50 wt% based on the total weight of the injectable particle.

7. The injectable particle of any one of claims 1 to 6, wherein the pH adjusting agent 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 particles, (b) biodegradation of all or a portion of the injectable particles, or (c) a combination of (a) and (b).

8. The injectable particle of any one of claims 1 to 7, wherein the injectable particle comprises a biostable core and a coating comprising the pH adjusting agent.

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

10. The injectable particle of any one of claims 8 to 9, wherein the biostable core comprises a polymer comprising one or more of methyl methacrylate monomers and vinyl alcohol monomers.

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

12. The injectable particle of any one of claims 8 to 11, wherein the coating further comprises a binder material or a matrix material.

13. The injectable particle of any one of claims 1 to 12, wherein said injectable particle further comprises at least one therapeutic agent.

14. The injectable particle of any one of claims 1 to 13, wherein said injectable particle further comprises at least one osmotic agent.

15. A container configured to be attached to a delivery catheter and preloaded with the injectable particle of any one of claims 1-14.

Background

Many clinical manifestations benefit from the modulation of the vascular, lymphatic or duct system by restricting the flow of body fluids or secretions. For example, the technique of embolization involves introducing microparticles into the circulation to occlude blood vessels, e.g., to stop or prevent bleeding or to cut off blood flow to structures or organs, as a means of limiting the access of essential oxygen and nutrients to the target tissue. Permanent or temporary closure of blood vessels is desirable for the control of various diseases and conditions.

In a typical embolization procedure, local anesthesia is first administered above the common artery. The artery is then percutaneously punctured and a catheter inserted, which is then guided to the region of interest using fluoroscopy. Angiography is then performed by injecting a contrast agent through the catheter. Embolic particles are then deposited through the catheter. Embolic particles are selected, for example, based on the size of the vessel to be occluded, the desired period of time for occlusion, and/or the type of disease or condition to be treated, among other factors. Subsequent angiograms are typically performed to determine the specificity and completeness of arterial occlusion.

Various polymer-based microspheres are currently used for embolization of blood vessels. Typically, these microspheres are guided through a microcatheter to a predetermined embolization site. Many commercially available embolic microspheres are constructed of polymers. Materials commonly used commercially for this purpose include polyvinyl alcohol (PVA), including acetalized PVA (e.g., Contour SE)^TMEmbolic agents, Boston Scientific, na-dick, massachusetts, usa), and crosslinked acrylic hydrogels available from Merit Medical Systems, ltd (south jordan, utah, usa) (e.g.,

microspheres ofEmbolic microspheres of triacrylic acid cross-linked with gelatin). Similar microspheres have been used in chemoembolization to increase the residence time of the therapeutic agent after delivery. In one particular case, the therapeutic agent (doxorubicin) has been added directly to the polyvinyl alcohol hydrogel microspheres so that it can be released locally after delivery (e.g., DC Bead)^TMDrug delivery chemoembolization system, biocompletics international publication limited, francam, salix county, uk). Other examples of embolic microspheres include those under the trade name

Commercially available from CeloNova BioSciences Inc. (St. Antonio, Tex.) having a utility

-F (poly [ bis (trifluoroethoxy) phosphazene)]) Coated hydrogel cores (e.g., embolization microspheres comprising methyl methacrylate polymers); under the trade name of Bead Block^TMEmbolic microspheres comprising an acrylamide-based PVA polymer, available from biocomplatibles International corporation (oxford, connecticut); and Quadra under the trade nameEmbolic microspheres comprising PVA-sodium acrylate copolymer are available from Merit Medical Systems limited (south geodan, utah, usa). Other examples of commercially available microspheres include microspheres containing embedded radioisotopes (e.g.,⁹⁰y) glass microspheres, in particular TheraSpheres^TMMDS Nordion, ottawa, canada; and containing a compound capable of chelating a radioisotope (a)⁹⁰Y) of a monomer, in particular SIR-

SIRTex Medical, Inc., New NanWales, Australia.

Embolizing microparticles have been used in hepatic arterial embolization (TAE) and hepatic arterial chemoembolization (TACE). The purpose of TACE or TAE surgery is to controllably localize tumorsThe microenvironment embolisms, effectively starving the tumor cells by removing upstream oxygen and glucose sources. However, tumor progression is known to lead to intratumoral lactic acidosis as a byproduct of the warburg effect and high levels of hypoxia. It has been postulated that TACE or TAE can increase hypoxia and the inability to flush lactic acid from tumors, and eventually the localization of this high concentration lactic acidosis decreases the rate of glycolysis, thereby decreasing the efficacy of TACE or TAE by turning cancer cells to a quiescent state, by halting the cells at G0/G1, and by reducing their dependence on glucose. See, e.g., Chao et al, "non-randomized cohort and randomized study of large liver cancer local control by targeting intratumoral lactic acidosis"Elife.2016, 8 months and 2 days; pii: e15691.Doi: 10.7554/eLife.15691. In other words, lactic acidosis, which is usually present in tumors and may be exacerbated by treatment with TAE or TACE, effectively prevents glucose starvation of cancer cells. It has further been postulated that this protection relies on the coexistence of lactate and hydrogen ions, and that removal of either will eliminate this effect. As above, see also Jiansheng Xie et al, "overriding the dual metabolic properties of Vanberg Effect-cancer cells" Scientific Reports, 4: paper No. 4927(2014), "DOI: 10.1038/srep04927 and Hao Wu et al," central role of lactic acidosis in the resistance of cancer cells to glucose deprivation leading to cell death,J Pathol.6 months 2012; 227(2) 189-99.doi: 10.1002/path.3978. Recently developed surgical procedures have been shown to improve clinical outcomes in patients with liver cancer, and better cellular responses and patient survival rates have been observed. Chao et al, supra. During this surgical step, 5% sodium bicarbonate can alternatively be infused with doxorubicin-iodinated oil emulsion and oxaliplatin/homocamptothecin and the dose adjusted to the tumor size, followed by PVA (r) ((r))

Microspheres) and microcoils (Tornado, cool Medical, usa) permanently embolize arteries. As above.

There is a continuing need in the art for improved injectable particles and methods of treatment using the particles to result in local modification of the tumor microenvironment to enhance the efficacy of glucose and oxygen limitation therapy.

Disclosure of Invention

According to some aspects, the present disclosure relates to injectable particles comprising at least one pH modifying agent for release from the injectable particles in vivo upon embolization of intratumoral arteries of a tumor with the injectable particles.

In various embodiments, the injectable particles may be spherical or non-spherical microparticles, and the injectable particles may have a diameter in the range of 20 micrometers (μm) or less to 5000 micrometers or more.

In various embodiments that may be applied in connection with any of the preceding aspects and embodiments, the injectable particles may be configured such that, upon embolization of an intratumoral artery of a tumor with the injectable particles, the injectable particles release the pH-modifying agent to form a microenvironment in the vascular bed of the tumor at a location downstream of the injectable particles having a pH that is higher than a pH that would exist in the absence of the pH-modifying agent (e.g., upon embolization with the same injectable particles except for the pH-modifying agent). Such a higher pH microenvironment may be maintained for at least 1 hour for up to 8 weeks or more, such as 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 the range between any two of the foregoing values), in some cases in the range of 2 weeks to 4 weeks.

In various embodiments that may be applied in connection with any of the preceding aspects and embodiments, the pH adjusting agent may be an alkaline agent having a pH of 7.5 or more (e.g., a pH dissolved in water at a concentration of 100mM at 25 ℃), in some cases in the range of 7.5 to 10.0.

In various embodiments that may be applied in combination with any of the preceding aspects and embodiments, the pH adjusting agent may be a pKa value having a pKa value of 7.6 or more, in some cases in the range of 7.6 to 35 (e.g., extrapolated to an infinite dilution in water at 25 ℃ (buffer concentration ═ 0), also referred to as pKa⁰Value) of a buffer.

In various embodiments that may be applied in combination with any of the preceding aspects and embodiments, the pH adjusting agent may 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).

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

In various embodiments that may be employed in connection with any of the preceding aspects and embodiments, the pH adjusting agent may be 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).

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

In various embodiments that may be employed in connection with any of the foregoing aspects and embodiments, the injectable particles may further comprise at least one therapeutic agent.

In various embodiments that may be employed in connection with any of the preceding aspects and embodiments, the injectable particles may further comprise at least one osmotic agent.

In other aspects of the present disclosure, the injectable particles according to any of the preceding 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 conduit (e.g., a syringe and other suitable containers).

In other aspects, the present disclosure is directed to methods 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, the pH modifying agent is released from the injectable particles, thereby forming a microenvironment with elevated pH in the vascular bed of the tumor at a location downstream of the injectable particles. For example, the pH of the microenvironment can be higher than would be present in the absence of a pH modifier (e.g., upon administration of injectable particles of the same composition except for the removal of the pH modifier).

In various embodiments, the pH adjusting agent is released for a period of at least one hour after administration of the injectable particles, for example, a period 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 the range between any two of the foregoing values) after administration of the injectable particles, in some cases a period in the range of 2 to 4 weeks after administration of the injectable particles.

In various embodiments, the pH modifying agent is released in the following manner: the pH of the microenvironment is maintained above the pH that would be present in the microenvironment in the absence of the pH modifier (e.g., the pH that would be present in the microenvironment if injectable particles of the same composition except for the pH modifier were administered) for a period of time of at least one hour after administration of the injectable particles, e.g., 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 after administration of the injectable particles (i.e., in a range between any two of the foregoing values), and in some cases in the range of 2 to 4 weeks after administration of the injectable particles.

The details of various aspects and embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

Detailed Description

The present disclosure relates to injectable particles comprising at least one pH modifying agent that is released at the site of action in vivo.

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

In certain embodiments, the injectable particles are designed such that upon intratumoral arterial embolization of a tumor with the injectable particles, the injectable particles release the at least one pH adjusting agent in such a way as to form a microenvironment in the vascular bed of the tumor at a location downstream of the injectable particles. In various embodiments, the microenvironment has a pH that is higher (e.g., at least 0.2pH units higher, preferably at least 0.5pH units higher) than the pH that would be present in the microenvironment in the absence of the pH modifying agent (e.g., a pH that is higher than the pH of the microenvironment formed in the vascular bed of the tumor at a location downstream of the injectable particle when embolized with injectable particles of the same composition except for the pH modifying agent). In certain of these embodiments, the injectable particles are configured to release the pH adjusting agent in an amount of: sufficient to maintain the pH of the microenvironment above the pH that would be present in the microenvironment in the absence of the pH modifier for at least 1 hour for 8 weeks or more, such as 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 to 4 weeks.

The injectable particles of the present disclosure can be used to treat various diseases and conditions in a variety of subjects. The subject includes vertebrate subjects, especially humans and various warm-blooded animals (including pets and livestock). As used herein, "treatment" refers to the prevention of a disease or condition, the alleviation or exclusion of symptoms associated with a disease or condition, or the apparent or complete exclusion of a disease or condition. Preferred treatments include embolization.

In certain embodiments, injectable particles according to the present disclosure may be used for TACE or TAE treatments. Because the injectable particles of the present disclosure contain a pH modifier that is released in vivo, such microparticles may be used in TACE and TAE procedures where the tumor microenvironment is embolized with the injectable particles while controlled adjustment of intratumoral pH is provided by the release of the in vivo pH modifier. Without wishing to be bound by theory, it is hypothesized that controlled adjustment of pH within the tumor to alkaline pH will reduce or rule out lactic acidosis effects, leading to higher glucose dependence and thus increased tumor cell death, resulting in more effective TACE and TAE treatment.

The pH adjusting agents useful in the present disclosure include a wide variety of organic and inorganic pH adjusting agents. In various embodiments, the pH adjusting agent used includes (a) a pH adjusting agent having (e.g., a pH at 25 ℃ at a concentration of 100mM in water) a pH greater than 7.4, typically an alkaline agent having a pH in the range of 7.5 to 10 (e.g., a pH in the range of 7.5 to 8.0 to 8.5 to 9.0 to 9.5 to 10) (which means that the selected pH range can be in a range between any two of the foregoing values); (b) a pH adjuster having (e.g. extrapolated to an infinite dilution in water (buffer concentration ═ 0) a pKa value at 25 ℃, which can also be referred to as pKa⁰A value) greater than 7.6, typically at least one pKa value 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) (which means that the selected pKa range may be in a range between any two of the foregoing values); and (c) a pH adjuster having both the pH of (a) and the pKa of (b).

Specific examples of the inorganic pH adjuster include: carbonates, e.g. sodium carbonate (pH 10.5, 25 ℃, 100mM in H)₂O), potassium carbonate (pH 10.5, 25 ℃ C., 100mM in H₂O) and calcium carbonate (pH 9.9, 25 ℃ C., 100mM in H₂O); and bicarbonate (also known as bicarbonate), such as sodium bicarbonate (pH 8.3, 25 ℃, 100mM in H₂O) and potassium bicarbonate (pH 8.3, 25 ℃ C., 100mM in H₂O), and the like. The carbonate acts as a buffer and there are two pKa values, one of which is bicarbonate<->Bicarbonate with pKa value of carbonic acid reaction and another pKa value<->pKa value of carbonate reaction. In the case of sodium bicarbonate, for bicarbonates<->pKa of carbonic acid reaction is-6.4 for bicarbonate<->The pKa of the carbonate reaction was 10.3.

Examples of inorganic pH modifiers also include phosphates, including dibasic phosphates, such as disodium hydrogen phosphate (pH 8.7-9.3, 25 ℃, 50mg/mL in H₂O) or dipotassium hydrogen phosphate (pH 8.7-9.3, 25 deg.C, 1M dissolved in H₂O), and the like. Phosphate acts as a buffer and there are three pKa values: one pKa is for phosphoric acid<->One for a base reaction, one pKa for a base<->Dibasic reaction and one pKa for the dibasic<->And (4) carrying out three-alkali reaction. In the case of sodium phosphates, for phosphoric acid<->pKa of monobasic reaction is-2.12 for monobasic<->The pKa of the dibasic reaction is 7.21, for dibasic reaction<->The pKa of the tribasic reaction was 12.67.

Other examples of inorganic pH adjusters include phosphazenes.

A variety of organic pH adjusting agents can be used in the present disclosure. In certain embodiments, one or more inorganic buffers are selected for use with the injectable particles. Suitable inorganic buffers may be selected from, for example, one or more of the following buffers, many of which are zwitterionic (each buffer is listed along with the reported pKa value at 25 ℃): 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), glycinamide (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- (cyclohexylamino) -1-ethanesulfonic acid) (9.4), ethanolamine (9.5), AMP (2-amino-2-methyl-1-propanol) (9.7), piperazine (9.7), glycine (9.8), CAPSO (9.8), 1, 3-diaminopropane (10.3), CAPS (3- (cyclohexylamino) -1-propanesulfonic acid) (10.5), cab (4- (cyclohexylamino) -1-butanesulfonic acid) (10.7), and piperidine (11.1), and pharmaceutically acceptable salts thereof, where applicable.

The aforementioned compounds are also generally alkaline agents.

As previously mentioned, the present disclosure is directed to injectable particles that release one or more pH modifying agents (e.g., selected from the foregoing, etc.) in vivo.

The pH adjusting agent may be released by any suitable mechanism: the mechanism includes (a) by diffusion from all or a portion of the injectable particles (e.g., where all or a portion of the injectable particles correspond to a matrix containing 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 a pH-adjusting agent and (ii) dissolve and/or biodegrade in vivo thereby releasing the pH-adjusting agent); or a combination of the foregoing; and other suitable mechanisms.

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

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

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

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 particles comprise a biostable core, and a coating layer that dissolves and/or biodegrades in vivo). As used herein, a microparticle or a portion thereof is "biodissolvable" if it loses a quantifiable mass. This process can occur in the range of hours to days to weeks to months to years. This degradation mechanism may result from mass or molecular weight loss. As used herein, a microparticle, or a portion thereof, is "biostable" if it is not "biodissolvable". In certain instances, 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.

Injectable particles and portions thereof (e.g., cores, coatings, etc.) according to the present disclosure can be constructed using a variety of inorganic materials (e.g., glass, ceramics, metals, etc.), organic materials (e.g., non-polymeric organic compounds, polymers, etc.), and combinations of inorganic and organic materials.

In various advantageous embodiments, injectable particles and portions thereof (e.g., cores, coatings, etc.) according to the present disclosure may be constructed using various polymers that may be biostable or biodissolvable. 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.

The injectable particles of the invention may be non-crosslinked, or they may be covalently 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.

Suitable organic materials for constituting the injectable particles and portions thereof (e.g., cores, coatings, etc.) may be selected from, for example, one or more of the following materials, many of which are polymers: polyphosphazines including poly [ bis (trifluoroethoxy) phosphazenes]And poly [ bis (ethylalanyl) phosphazene](poly[bis(ethyl alanato)phosphazene]) (ii) a Vinyl monomer homopolymers and copolymers, including condensation-acetalized vinyl alcohol homopolymers and copolymers (e.g., copolymers of vinyl alcohol with acrylic acid and salts thereof, copolymers of vinyl alcohol with 2-acrylamido-2-methylpropanesulfonic acid and salts thereof, and the like), polyvinyl ketones, polyvinyl carbazoles, 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 aromatic hydrocarbons (e.g., polystyrenes, styrene-maleic anhydride copolymers), vinyl aromatic hydrocarbon-olefin copolymers, including styrene-butadiene copolymers, styrene-ethylene-butylene copolymers (e.g., polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymers, by commodity name

G series polymers), 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. patent No. 6,545,097 to Pinchuk); siloxane polymers and copolymers; polycarboxylic acid polymers and copolymers, including homopolymers and copolymers of polyacrylic and polymethacrylic acids, and salts thereof, ethylene-methacrylic acid copolymers and ethylene-acrylic acid copolymers, wherein some of the acid groups may 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-propiophenone 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, glassPapers, rayon (rayon), rayon triacetate, and cellulose ethers (such as carboxymethylcellulose and hydroxyalkylcellulose), polyoxymethylene polymers and copolymers, polyimide polymers and copolymers (such as polyether block amides, polyamideimides, polyesterimide imides, and polyetherimides), polyamide polymers and copolymers, including nylon 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 polymers, and copolymers of α -hydroxy acids, such as polylactic acid (including dextrorotatory, levorotatory, and meso forms), polyglycolide and polyethylene propylene, epsilon-caprolactone, polylactide-caprolactone, polyhydroxybutyrate, polyhydroxyvalerate, poly (p-dioxanone), trimethylene carbonate (and its alkyl derivatives), polymers, 1, 4-dioxanone-cycloheptane-2, 1-5, and poly (ethylene-propylene-ethylene-co-ether), poly (ethylene-propylene-ethylene-co-ethylene-propylene-ethylene-propylene-carbonate), poly (ethylene-propylene-ethylene-co-ethylene-propylene-ethylene-carbonate), poly (ethylene-propylene-ethylene-propylene-carbonate), poly (ethylene-propylene-ethylene-propylene-2-propylene-ethylene-propylene-ethylene-2, poly (ethylene-propylene-ethylene-propylene-2-ethylene-propylene-ethylene-propylene-ethylene-propylene-ethylene-propylene-ethylene-propylene-oxide, ethylene-propylene-ethylene-propylene-Polymers and mixtures thereof; a parylene polymer; a polycarbonate resin; (polyether-polyester) copolymers such as polyethylene oxide-polylactic acid copolymers; polyalkylene oxalates; polyoxamides and polyoxaesters (including those containing amino and/or amide groups); a poly (ortho) acid; waxes, such as paraffin wax; biopolymers such as polypeptides, proteins, polysaccharides and fatty acids (and esters thereof) including gelatin, starch, collagen, polyglycosides, fibrin, fibrinogen, elastin, alginic acid, chitosan, glycosaminoglycans such as hyaluronic acid, and mixtures of the foregoing.

In certain embodiments where a biodegradable polymer is used, it may be desirable to use a biodegradable polymer having non-acidic degradation products. Examples of biodegradable polymers reported to have non-acidic degradation products include polyacetals, polyketides (e.g., poly (1, 4-phenylpropanedimethyleneketal), poly (cyclohexane-1, 4-diylacetonedimethyleneketone, etc.), polyphosphazenes (e.g., poly [ bis (ethylacryloyl) phosphazene ], etc.), polyimides, polyhydrazones, and polyorthoesters, etc.

In certain embodiments, the injectable particles may comprise one or more coatings surrounding the core, at least one coating comprising a pH adjusting agent. Such a coating containing a pH adjuster can consist essentially of the pH adjuster (e.g., can contain at least 90 wt.%, at least 95 wt.%, or at least 99 wt.% of the pH adjuster), or can contain the pH adjuster in admixture with one or more other materials that can be selected from, for example, small molecule inorganic compounds, biostable polymers, and biodegradable polymers, such as binder materials and matrix materials.

In some embodiments, known injectable particles may be coated with a coating containing one or more pH adjusting agents. Examples of such injectable particles include various polymer-based microspheres that are used to embolize 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 salts thereof (e.g., Quadra)

) Microspheres of copolymers of vinyl alcohol and 2-acrylamido-2-methylpropanesulfonic acid and salts thereof (e.g., Bead Block)^TM) Microspheres composed of a triacrylate crosslinked with gelatin (e.g.,

) And comprising the use of poly [ bis (trifluoroethoxy) phosphazene]Coated microspheres comprising a hydrogel core of methyl methacrylate (e.g.,) And the like.

In some embodiments, the injectable particles of the present disclosure comprise an osmotic agent. The osmotic agent may be added to increase the osmotic pressure in the hydration layer associated with the microparticles, which will increase the release of the pH modifying agent from the microparticles, thereby improving the penetration of the pH modifying agent comprising the buffer into the tumor tissue. The injectable particles, if present, may comprise an osmotic agent in an amount ranging from 5% to 40% based on the total weight of the injectable particles.

Examples of the osmotic pressure agent include: inorganic salts such as sodium chloride, potassium chloride, sodium phosphate, potassium phosphate and the like; and organic osmolytes including sugars (e.g., fructose, sucrose, dextrose, lactose, and the like); sugar alcohols (e.g., ethylene glycol, xylitol, sorbitol, mannitol, etc.); amino acids (e.g., L-arginine, etc.); and combinations thereof.

In some embodiments, the injectable particles of the present disclosure may comprise one or more therapeutic agents. If present, the injectable particle may comprise a therapeutic agent in an amount ranging from 0.0001% to 25% based on the total weight of the injectable particle (e.g., 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%) (which means that the selected amount may range between any two of the recited values).

Examples of therapeutic agents that may be used in the embolizing compositions of the invention include toxins (e.g., ricin, radioisotopes, or any other drug capable of killing the undesirable cells that make up cancers and other tumors (e.g., uterine fibroids)), and drugs that prevent the growth of undesirable cells.

Specific examples of therapeutic agents may be selected from the following suitable members: antineoplastic/antiproliferative/antimitotic agents, including antimetabolites such as folic acid analogs/antagonists (e.g., methotrexate, etc.), purine analogs (e.g., 6-mercaptopurine, thioguanine, cladribine (which is a chlorinated purine nucleoside analog), etc.), and pyrimidine analogs (e.g., cytarabine, fluorouracil, etc.); alkaloids include taxanes (e.g., paclitaxel, docetaxel, etc.); alkylating agents such as alkyl sulfonates, nitrogen mustards (e.g., cyclophosphamide, ifosfamide, etc.), nitrosoureas, ethylene imines and methyl melamines, 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.), antineoplastic enzymes (e.g., asparaginase, etc.), agents that affect microtubule dynamics (e.g., vinblastine, vincristine, colchicine, Epo D, epothilone), caspase activators, proteasome inhibitors, angiogenesis inhibitors (e.g., statins such as endostatin, cerivastatin and angiostatin, squalamine, etc.), rapamycin (sirolimus) and analogs thereof (e.g., everolimus, tacrolimus, zotarolimus, and the like), etoposide, and many other drugs (e.g., hydroxyurea, fradapine, procarbazine, mitoxantrone, camptothecin, and the like), various pharmaceutically acceptable salts and derivatives of the foregoing (e.g., esters, and the like), and combinations of the foregoing, and other agents. Other examples of therapeutic agents include radioisotopes including⁹⁰Y、³²P、¹⁸F、¹⁴⁰La、¹⁵³Sm、¹⁶⁵Dy、¹⁶⁶Ho、¹⁶⁹Er、¹⁶⁹Yb、¹⁷⁷Lu、¹⁸⁶Re、¹⁸⁸Re、¹⁰³Pd、¹⁹⁸Au、¹⁹²Ir、⁹⁰Sr、¹¹¹In or⁶⁷Ga, and biological agents, such as immunotherapeutic antibodies or other biological components.

In some embodiments, the injectable particles of the present disclosure comprise a substance that increases the radiopacity of the microparticles (i.e., makes the polymer more X-ray absorbing and therefore visible under X-ray imaging techniques such as X-ray fluoroscopy and the like). Examples of radiopaque agents include metals, metal salts and metal oxides, and iodinated compounds. More specific examples of such radiopacifiers include gold, tungsten, platinum, tantalum, iridium, or other dense metals, barium sulfate, bismuth subcarbonate, bismuth trioxide, bismuth oxychloride, metrizamide, iopamidol, sodium iodophthalein, sodium iodoamide, and meglumine. The injectable particle, if present, may contain a radiopacifier in an amount ranging from 0.01% to 40% based on the total weight of the injectable particle.

Injectable particle compositions according to the present disclosure may be stored and transported in a sterile dried form. The dried composition can be shipped, for example, in a catheter, syringe, vial, ampoule, or other container (e.g., any container configured to interact with a delivery catheter), and it can be mixed with a suitable liquid carrier (e.g., sterile water for injection, physiological saline, phosphate buffer, a solution containing an imaging contrast agent, etc.) prior to administration. Thus, the concentration of the composition to be injected can be varied at will by the physician in charge of the surgery, according to the specific use under way. The liquid carrier of one or more containers may also be provided and transported in a kit along with the dried particles.

In other embodiments, the injectable particles can be stored in a sterile suspension comprising water and injectable particles. As noted above, the suspending agent may be stored in, for example, a catheter, syringe, vial, ampoule, or other container. The suspension may also be mixed with a suitable liquid carrier (e.g., sterile water for injection, physiological saline, phosphate buffer, solutions containing contrast agents, etc.) prior to administration, thereby allowing the concentration of the administered microparticles in the suspension to be reduced prior to injection, if desired by the physician responsible for the procedure. One or more containers of liquid carrier may also be provided to form a kit.

The present invention includes various methods of administering the injectable particles of the present invention to effect embolization or another procedure that benefits from injectable particles of the present disclosure. One skilled in the art can determine the most desirable method of administering the microparticles based on the type of treatment and the condition of the patient, among other factors. Methods of administration include, for example, transdermal methods, as well as other effective routes of administration. For example, the particulate compositions of the present invention may be delivered via a syringe or via a catheter (e.g., a microcatheter) that may be advanced over a guidewire, steerable microcatheter, or flow-guided microcatheter, among other devices.