Radiation-impermeable components

Abstract

In some embodiments, the present disclosure relates to a medical liquid composition comprising (a) a polymer, a monomer, a macromonomer, or a combination of any two or all three thereof, and (b) spherical metal particles, which may include, for example, tantalum, tungsten, rhenium, niobium, molybdenum, and alloys thereof. In some embodiments, the present disclosure relates to a medical method comprising administering such a liquid composition to a patient. In some embodiments, the present disclosure relates to the use of such a liquid composition as a liquid embolic agent, fiducial marker, tissue barrier material, or therapeutic agent depot. In some embodiments, the present disclosure relates to a medical device comprising a coating formed from such a liquid composition.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to radiopaque compositions comprising polymers and spherical metal particles, and particularly to their use in medical methods and in the manufacture of medical devices, including therapeutic embolization. [Background technology]

[0002] Spherical tantalum particles, also known as spherical tantalum powder or tantalum microspheres, are produced by plasma inert gas atomization of conventional tantalum particles, such as angular or nodular tantalum powder. Existing applications for spherical tantalum include sputtering targets, high-temperature or corrosion-resistant coatings, and alloy additives. Articles such as implants can be made entirely from 3D-printed tantalum, which has excellent biocompatibility and helps promote bone ingrowth.

[0003] Therapeutic embolization is a minimally invasive procedure that creates an obstruction by introducing material into blood vessels to slow or stop blood flow or fill spaces such as aneurysms. This technique is useful in treating conditions such as gastrointestinal bleeding, arteriovenous malformations, hypervascular tumors, benign tumors such as uterine fibroids, and benign prostatic hyperplasia (BPH). Summary of the Invention

[0004] In some embodiments, the present disclosure relates to a medical liquid composition comprising (a) a polymer, a monomer, a macromonomer, or a combination of any two or all three thereof, and (b) spherical metal particles (also sometimes referred to herein as spherical metal powder or metal microspheres). In some of these embodiments, the spherical metal particles are selected from tantalum, tungsten, rhenium, niobium, molybdenum, and alloys thereof.

[0005] In some embodiments that can be used in combination with any of the above embodiments, the spherical metal particles have a median particle size in the range of 1 to 10 μm. In some embodiments that can be used in combination with any of the above embodiments, the spherical metal particles have an average aspect ratio in the range of 1.0 to 1.25.

[0006] In some embodiments that can be used in combination with any of the above embodiments, the spherical metal particles have D10 and D90 values ​​that are within 50% of the median diameter. In some embodiments that can be used in combination with any of the above embodiments, the spherical metal particles have a median particle size in the range of 1 to 10 μm.

[0007] In some embodiments, the liquid composition may contain the spherical metal particles in a range of 0.1 g / ml or less to 0.9 g / ml or more, for example, 0.1 g / ml to 0.2 g / ml to 0.3 g / ml to 0.4 g / ml to 0.5 g / ml to 0.6 g / ml to 0.7 g / ml to 0.8 g / ml to 0.9 g / ml (in other words, a range between any two of the aforementioned values).

[0008] In some embodiments that can be used in combination with any of the above embodiments, the liquid composition is a sterile, injectable liquid composition that solidifies in situ upon injection into a subject.

[0009] In some embodiments that can be used in combination with any of the above embodiments, the liquid composition may be provided in a syringe. In some embodiments that can be used in combination with any of the above embodiments, the liquid composition is a precipitating liquid composition comprising the spherical metal particles, the polymer, and a carrier solvent comprising a water-miscible organic solvent in which the polymer is dissolved.

[0010] In some embodiments that can be used in combination with any of the above embodiments, the liquid composition is a gelled liquid composition comprising the spherical metal particles, the polymer, and a carrier solvent in which the polymer is dissolved. The carrier solvent can be an aqueous solvent or a water-miscible organic solvent. In some embodiments, the polymer in the gelled liquid composition forms a gel upon contact with a gelling agent. In some embodiments, the gelling agent is a crosslinking agent. In some of these embodiments, the gelling agent is naturally present in bodily fluids. In some embodiments, the polymerizable liquid composition is part of a system that includes an additional liquid composition that includes the gelling agent.

[0011] In some embodiments that can be used in combination with any of the above embodiments, the liquid composition is a polymerizable liquid composition comprising the spherical metal particles, the monomer and / or the macromonomer, and optionally a carrier solution. In these embodiments, the monomer and / or the macromonomer polymerizes upon contact with the polymerization initiator. In some of these embodiments, the polymerization initiator is naturally present in bodily fluids. In some of these embodiments, the polymerizable liquid composition is part of a system that includes an additional liquid composition that includes the polymerization initiator.

[0012] In some embodiments that can be used in combination with any of the above embodiments, the liquid composition is a polymer composition capable of undergoing a sol-gel phase transition in response to in vivo conditions, including temperature, ionic strength, and / or pH. This composition comprises the spherical metal particles, the polymer capable of a sol-gel phase transition, and optionally a carrier solution. In these embodiments, the polymer is typically a block copolymer comprising at least an A block and a B block. Examples of such polymers are described in U.S. Patent Nos. 6,562,362, 6,660,247, 6,784,266, 7,485,317, and 7,025,990.

[0013] In some embodiments that can be used in combination with any of the above embodiments, the polymer is a hydrophilic polymer or a hydrophobic polymer, hi some embodiments, at least a portion of the polymer comprises a vinyl alcohol homopolymer or copolymer.

[0014] In some embodiments that can be used in combination with any of the above embodiments, the macromer is a hydrophilic macromer or a hydrophobic macromer, hi some embodiments, at least a portion of the macromer comprises a homopolymer or copolymer of vinyl alcohol.

[0015] In some embodiments that can be used in combination with any of the above embodiments, at least a portion of the polymer comprises pendant iodine-containing groups. In some embodiments, which can be used in combination with any of the above embodiments, at least some of the macromers include pendant iodine-containing groups.

[0016] In some embodiments, which can be used in combination with any of the above embodiments, the liquid composition further comprises a therapeutic agent. In some embodiments, the present disclosure relates to a method of embolizing tissue, comprising delivering a liquid composition of any of the above embodiments into a vasa vasorum of the tissue.

[0017] In some embodiments, the present disclosure relates to a method of treatment comprising delivering the liquid composition of any of the above embodiments into a tumor of a patient, wherein the therapeutic agent is released into the tumor. In some embodiments, the present disclosure relates to a method for local or systemic therapeutic agent release comprising delivering the liquid composition of any of the above embodiments to a patient in need thereof.

[0018] In some embodiments, the present disclosure relates to a method of separating a first tissue from a second tissue, comprising delivering a liquid composition of any of the above embodiments between the first tissue and the second tissue.

[0019] In some embodiments, the present disclosure relates to the use of the liquid composition of any of the above embodiments as a liquid embolic agent, fiducial marker, tissue separating material, or therapeutic agent depot. In some embodiments, the present disclosure relates to a medical device comprising a coating formed from the liquid composition of any of the above embodiments. [Brief explanation of the drawings]

[0020] [Figure 1] Figure 1A is an image showing the string in the tensile test setup, and Figure 1B is an image showing the uniform distribution of spherical Ta particles at a microscopic level. [Figure 2A] 10 is a microscopic image of a string containing no Ta particles (the tensile testing apparatus is shown in the inset). [Figure 2B] 1 is a microscope image of a string with spherical Ta particles. [Figure 2C] 1 is a microscope image of a string with agglomerated Ta particles. [Figure 3A] Micro-computed tomography (μCT) images of samples containing spherical and agglomerated Ta particles are shown with values ​​reported in grayscale and Hounsfield units. [Figure 3B] A micro-computed tomography (μCT) image of a sample containing crushed Ta particles is shown with values ​​reported in grayscale and Hounsfield units. [Figure 4A] 3B shows an X-ray shadowgraph of the sample shown in FIG. 3A. [Figure 4B] 3B shows an X-ray shadowgraph of the sample shown in FIG. 3B. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description In various aspects, the present disclosure relates to liquid compositions for medical applications comprising (a) a polymer, a monomer, a macromonomer, or a combination thereof, and (b) spherical metal particles. In some embodiments, the spherical metal particles have a median particle size in the range of 1 to 10 μm.

[0022] Spherical metal particles for use in the present disclosure include spherical metal particles formed from tantalum, tungsten, rhenium, niobium, molybdenum, and alloys thereof. In certain embodiments, the spherical metal particles are formed from tantalum or tantalum alloys.

[0023] Spherical metal particles for use in this disclosure have a generally spherical shape, including spheres, oblate spheroids, and prolate spheroids. Median particle size and particle size distribution can be measured by laser diffraction and expressed as particle size (horizontal axis) versus volume percentage (vertical axis). Here, D10 is the diameter at which 10% by volume of particles have a diameter below this value; D50 is the diameter at which 50% by volume of particles with a smaller diameter and 50% by volume of particles with a larger diameter (also referred to herein as the median diameter); and D90 is the diameter at which 90% by volume of particles have a diameter below this value. More specifically, laser diffraction measures particle size distribution by measuring the angular variation in the intensity of scattered light as a laser beam passes through a dispersed particle sample. Larger particles scatter light at smaller angles relative to the laser beam, while smaller particles scatter light at larger angles. The angular scattering intensity data is then analyzed, and the size of the particles responsible for creating the scattering pattern is calculated using the Mie theory of light scattering. Particle size is reported as the diameter of a volume-equivalent sphere.

[0024] In some embodiments, the D10 and / or D90 of the spherical metal particles can be within 50%, 40%, 30%, 25%, 20%, 15%, 10%, or 5% of the median diameter (D50).

[0025] In some embodiments, the spherical metal particles of the present disclosure can be defined by their average aspect ratio. The average aspect ratio of spherical metal particles is defined herein as the ratio of the largest linear dimension of a spherical metal particle (i.e., tantalum powder) to the smallest linear dimension of the same spherical metal particle, based on random measurements of 50 or 100 particles, or random measurements of about 1% to about 2% by weight of a batch of spherical metal particles. Measurements of spherical metal particles are performed using scanning electron microscope (SEM) images. Perfectly spherical particles have an aspect ratio of 1.0. In various embodiments, the spherical metal particles have an average aspect ratio ranging from 1.0 to 1.25, 1.0 to 1.15, or 1.0 to 1.1.

[0026] Liquid compositions of the present disclosure include those suitable for injection into the body. In various embodiments, such liquid compositions form a solid material in situ after injection into the body. For example, some of these liquid compositions rely on polymerization or gel formation to form a solid material in situ, while other liquid compositions rely on delivery of a polymeric material in a carrier, such as an organic solvent, leaving behind a solid material after the carrier dissipates within the body.

[0027] Because the compositions of the present disclosure contain metal particles, they have enhanced radiopaque properties, allowing them to be visualized (or made more visible) under x-ray. In some embodiments, the liquid composition can contain 0.1 to 0.9 g / ml of spherical metal particles.

[0028] The liquid compositions of the present disclosure can be used in many applications, including as liquid embolic compositions, fiducial markers, tissue barriers, and depots containing therapeutic agents from which the therapeutic agents elute into surrounding tissue. The liquid compositions of the present disclosure can also be used to form coatings for medical devices.

[0029] In embodiments in which a liquid composition of the present disclosure is injected into a subject's body, the liquid composition can be adapted to pass through the particular delivery device used for injection, preferably by manual pressure. The desired viscosity level typically varies depending on the procedure and delivery method. For direct injection with a needle and syringe, the amount of pressure required varies, for example, depending on the gauge of the needle. Similarly, for injection through a catheter, the amount of pressure required varies, for example, depending on the inner diameter of the catheter. In various embodiments, the viscosity of the liquid composition ranges from 100 mPa·s or less to 20,000 mPa·s or more at 25°C, e.g., from 100 mPa·s to 200 mPa·s to 500 mPa·s to 1000 mPa·s to 2000 mPa·s to 5000 mPa·s to 10000 mPa·s to 20000 mPa·s at 25°C, more typically from 100 to 5000 mPa·s at 25°C.

[0030] The liquid compositions of the present disclosure may be provided in a sterile form. As already indicated, the presence of spherical metal particles in the compositions of the present disclosure is advantageous in that the particles render such compositions more radiopaque during interventional procedures and after implantation within the body.

[0031] The presence of spherical metal particles in the liquid compositions of the present disclosure is also advantageous in that it improves the processability of the liquid compositions. For example, the particles are easily dispersed without the need for sonication and have stable and predictable settling times, thereby improving the formulation of the liquid compositions during use.

[0032] The spherical nature of the particles also reduces particle agglomeration in both the liquid composition and the solid composition formed therefrom. As a result of reduced agglomeration, the liquid composition has improved flow characteristics, allowing it to flow more easily through a given delivery device, reducing injection forces and the likelihood of clogging within the delivery device. Improved flow also allows the liquid composition to more easily flow into the body cavity into which it is injected, subsequently filling and conforming to the cavity. Furthermore, by selecting spherical metal particles with a uniform particle size distribution, the particles are more tightly and uniformly packed after the composition solidifies in situ, providing the resulting implant with improved mechanical properties and enhanced radiopacity, as well as potentially reducing x-ray artifacts (agglomeration can cause x-ray clustering and streak artifacts).

[0033] As noted above, liquid compositions of the present disclosure include those that solidify in situ through various processes, including liquid compositions that precipitate, gel, and / or polymerize in situ upon injection into the body.

[0034] In some embodiments, the liquid composition of the present disclosure is a precipitating liquid composition comprising the spherical metal particles described above, at least one polymer, and a carrier solvent comprising one or more organic solvents in which the at least one polymer is dissolved. In some embodiments, the one or more organic solvents are water-miscible organic solvents. Water-miscible means that 0.5 ml of the solvent will completely dissolve in 1 liter of phosphate-buffered saline (137 mM NaCl, 2.7 mM KCl, 10 mM NaHPO, and 1.8 mM KHPO) at 20°C. Examples of suitable organic solvents include biocompatible polar aprotic solvents, such as dimethyl sulfoxide, dimethylformamide, N,N'-dimethylpropylene urea, 1,3-dimethyl-2-imidazolidinone, glycerol, ethyl lactate, N-methyl-2-pyrrolidone, and 2-(oxolan-2-ylmethoxy)ethanol. The one or more solvents are typically selected from dimethyl sulfoxide and N-methyl-2-pyrrolidone, more typically dimethyl sulfoxide. In some embodiments, the carrier solvent can include water (e.g., up to 80% v / v water) in addition to one or more organic solvents. In other embodiments, the carrier solvent is water-free. Typically, the precipitable liquid composition includes at least one polymer dissolved in a solvent at a concentration of 2% wt / wt or less to 50% wt / wt or more, e.g., 2% wt / wt to 5% wt / wt to 10% wt / wt to 25% wt / wt to 50% wt / wt of at least one polymer dissolved in a solvent, more typically 3 to 35% wt / wt of at least one polymer dissolved in a solvent.

[0035] When the presently disclosed precipitating liquid composition comes into contact with an environment that stimulates precipitation, such as a physiological fluid, precipitation of the previously dissolved polymer occurs, forming a solid in situ. During solidification, the carrier solvent diffuses out of the precipitating liquid composition. Additionally, diffusion of precipitating species (e.g., non-solvent water or ions) from the body may diffuse into the precipitating liquid composition. The precipitating liquid composition offers the advantage of solidifying only upon contact with the precipitating stimulus provided by physiological fluid, thus avoiding the problem of clotting within the delivery device, which could lead to the risk of clogging the delivery device. In the case of embolization, this characteristic allows delivery to be paused during the procedure, for example, to prevent material from entering non-target vessels and allow for better control.

[0036] In various embodiments, the polymers used in the liquid compositions of the present disclosure, including the precipitable liquid compositions described above, can be selected from a variety of synthetic, natural, or synthetic-natural hybrid hydrophilic or hydrophobic polymers. Examples of polymers include, for example, vinyl alcohol homopolymers and copolymers, including poly(vinyl alcohol) (PVA) and ethylene-vinyl alcohol (EVA); alkylene oxide homopolymers and copolymers, including poly(ethylene oxide), poly(propylene oxide), and poly(ethylene oxide-co-propylene oxide); vinylpyrrolidone polymers and copolymers, including poly(vinylpyrrolidone) (PVP); allyl alcohol homopolymers and copolymers, including poly(allyl alcohol); ethyleneimine homopolymers and copolymers, including poly(ethyleneimine); allylamine homopolymers and copolymers, including poly(allylamine); vinylamine homopolymers and copolymers, including poly(vinylamine); poly(2-alkyl-2-oxazolines), such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-methyl-2-oxazoline). Examples of suitable polymers include oxazoline homopolymers and copolymers, including poly(N-isopropylacrylamide) (PNIPAM) and poly(2-propyl-2-oxazoline); acrylamide homopolymers and copolymers, including poly(N-isopropylacrylamide) (PNIPAM) and polyacrylamide (PAM); acrylate homopolymers and copolymers, including hydroxyalkyl acrylate (e.g., hydroxyethyl acrylate, hydroxypropyl acrylate, etc.) homopolymers and copolymers of acrylic acid; methacrylate homopolymers and copolymers, including hydroxyalkyl methacrylate (e.g., hydroxyethyl methacrylate, hydroxypropyl methacrylate, etc.) homopolymers and copolymers and methacrylic acid homopolymers and copolymers; amino acid homopolymers and copolymers; saccharide homopolymers and copolymers; and combinations thereof. In various embodiments, the polymers used in the liquid compositions of the present disclosure are biostable.

[0037] In certain embodiments, the polymers used in the precipitating liquid compositions of the present disclosure include homopolymers and copolymers of hydroxyethyl methacrylate. In certain embodiments, polymers used in the presently disclosed precipitating liquid compositions include vinyl alcohol homopolymers and copolymers, including poly(vinyl alcohol) and poly(ethylene-vinyl alcohol). The vinyl alcohol polymers used in the precipitating liquid compositions described herein, particularly those comprising poly(vinyl alcohol) and poly(ethylene-vinyl alcohol), are typically not crosslinked.

[0038] Poly(vinyl alcohol) homopolymers suitable for use in the present disclosure can be of any suitable molecular weight. In some useful embodiments, poly(vinyl alcohol) homopolymers can have a weight average molecular weight ranging from 1 kDa or less to 250 kDa or more, e.g., from 1 kDa to 2.5 kDa to 5 kDa to 10 kDa to 25 kDa to 50 kDa to 100 kDa to 250 kDa. In some useful embodiments, they can have a weight average molecular weight of (a) at least 3 kDa, typically at least 5 kDa, more typically at least 10 kDa, and (b) up to 150 kDa, more typically up to 100 kDa, and even more typically up to 75 kDa.

[0039] In some embodiments, the liquid composition is a gelled liquid composition comprising the spherical metal particles described above, a polymer, and a carrier solvent in which the polymer is dissolved. The carrier solvent may be an aqueous solvent or a water-miscible organic solvent as described elsewhere herein. In some embodiments, the polymer forms a gel upon contact with a gelling agent. In some embodiments, the gelling agent is a crosslinking agent. In some of these embodiments, the gelling agent is naturally present in bodily fluids (e.g., divalent and multivalent cations found in bodily fluids). In some embodiments, the gelling agent is delivered.

[0040] In certain embodiments, the polymer used in the gelled liquid compositions of the present disclosure comprises or is a polysaccharide, hi some embodiments, the polymer may be, for example, alginate, gellan gum, guar gum, xanthan gum, welan gum, chitosan, hyaluronic acid, or starch, or a mixture thereof, particularly alginate or gellan gum.

[0041] In some embodiments where the polymer is a polysaccharide, the solvent is an aqueous solvent such as water. The aqueous solution may include a buffering agent such as a phosphate buffer or other pharmaceutically acceptable buffer. Polysaccharides can form gels when contacted with gelling agents, including divalent and multivalent cations such as calcium, barium, and strontium ions, which are useful for gelling negatively charged polysaccharides such as alginate and gellan gum.

[0042] In some of these embodiments, the gelled liquid composition is part of a system that includes an additional liquid composition that includes a gelling agent, hi some embodiments, the additional liquid composition that includes a gelling agent is an aqueous composition.

[0043] In some embodiments, the gelling liquid composition is a polymer composition capable of undergoing a sol-gel phase transition in response to in vivo conditions, including temperature, ionic strength, and / or pH. In some embodiments, the polymer composition is capable of undergoing a sol-gel phase transition in response to both pH and temperature. Such compositions are liquid at 20°C before delivery to the body and become gel at 37°C and pH 7. The composition comprises spherical metal particles, a polymer capable of undergoing a sol-gel phase transition, and typically a carrier solution. In some embodiments, the carrier solution is an aqueous carrier solution, which may comprise a pharmaceutically acceptable buffer. In some embodiments, the polymer is a block copolymer, such as an ABA triblock copolymer. In some embodiments, the B block is a pH-responsive block and the A block is a temperature-sensitive block.

[0044] In some embodiments, the liquid composition of the present disclosure is a polymerizable liquid composition comprising (a) the spherical metal particles described above, (b) one or more monomers and / or macromonomers, and (c) optionally a carrier solution. The monomers and / or macromonomers polymerize upon contact with a suitable polymerization initiator.

[0045] In certain embodiments, the monomers and / or macromonomers of the polymerizable liquid compositions of the present disclosure polymerize upon contact with an initiator present in a bodily fluid. In some of these embodiments, the polymerizable liquid composition may be a liquid embolic composition, in which the monomers in the composition, when introduced into the vasculature, polymerize under conditions found in blood to form emboli within the vasculature. One example of such a polymerizable liquid composition is one that includes one or more cyanoacrylate monomers, such as N-butyl-2-cyanoacrylate. In embodiments in which the polymerizable liquid composition is a liquid embolic composition, upon injection into the vasculature, the N-butyl-2-cyanoacrylate monomer rapidly polymerizes under conditions found in blood (i.e., in the presence of water) to form emboli within the vasculature. A fast polymerization rate can be beneficial in situations requiring rapid embolization, such as for trauma or gastrointestinal bleeding.

[0046] In some embodiments, the monomers and / or macromonomers of the polymerizable liquid composition of the present disclosure polymerize upon contact with a polymerization initiator present in an additional liquid composition. In some embodiments, the polymerizable liquid composition of the present disclosure is part of a system that further includes an additional liquid composition comprising a polymerization initiator. The polymerizable liquid composition can be combined with the additional liquid composition before or during delivery to a patient. The polymerizable liquid composition and the additional liquid composition can also be delivered sequentially to a patient such that the polymerizable liquid composition and the additional liquid composition are mixed in situ within the patient's body.

[0047] Examples of such polymerization initiators include free radical initiators. Examples of such monomers include, among others, free radically polymerizable monomers such as acylate monomers, methacrylate monomers, and vinyl monomers. Examples of such macromonomers include, among others, free radically polymerizable macromers, including polymers further comprising free radically polymerizable groups. Such macromonomers include, among others, acylate-terminated macromonomers, methacrylate-terminated macromonomers, and vinyl-terminated macromonomers. Polymers that can be functionalized with polymerizable groups to form macromonomers can be selected from the polymers described above. Examples of free radically polymerizable polymers, particularly those used as liquid emboli, can be found in WO 01 / 68720, which discloses free radically polymerizable PVA macromers and is incorporated herein by reference in its entirety.

[0048] In embodiments where the liquid composition is a polymerizable liquid composition that is combined with an additional liquid composition including a polymerization initiator prior to delivery to a patient, or a gelled liquid composition where the liquid composition is combined with an additional liquid composition including a gelling agent prior to delivery to a patient, the components are selected so that the material solidifies over a predictable, predetermined period of time. In these embodiments, delivery should be carried out within a limited time frame to avoid clogging the device delivering the liquid composition due to the mixed composition solidifying within the device.

[0049] In some embodiments, the polymerizable liquid composition is combined with an additional liquid composition comprising a polymerization initiator during delivery to a patient, or the gelled liquid composition is combined with an additional liquid composition comprising a gelling agent during delivery to a patient. Delivery of these liquid compositions and additional liquid compositions through a dual lumen device ensures that the reactive components remain separated during delivery until they are mixed at the distal end of the device.

[0050] Polymers and macromers used in the liquid compositions of the present disclosure, including those described above, among others, can be imparted with a degree of radiopacity by providing the polymers and macromers with pendant iodine-containing groups, e.g., by attaching pendant iodine-containing groups along the polymer or macromer backbone. In some embodiments, the polymers and macromers in the liquid compositions of the present disclosure can include (a) polymers and macromers, such as those described above, among others, that include pendant phenyl groups substituted with one or more iodine atoms, (b) polymers and macromers, such as those described above, among others, that include pendant phenyl groups substituted with one or more iodine atoms and pendant phenyl groups substituted with one or more hydrophilic moieties (e.g., moieties containing -OH, -COOH, -SOH, and / or -OPOH groups), and (c) polymers and macromers, such as those described above, among others, that include pendant phenyl groups substituted with both (i) one or more iodine atoms and (ii) one or more hydrophilic moieties. Certain embodiments include iodinated hydroxyethyl methacrylate copolymers, such as the copolymer of 2,4,6-triiodophenol-lactide-lactide-co-glycolic acid acrylate and hydroxyethyl methacrylate found in the precipitating hydrophobic injectable liquid PHIL® (MicroVention, Tustin, CA, USA). Certain embodiments also include iodinated vinyl alcohol polymers and copolymers. Liquid embolic formulations that do not contain spherical metal particles and that include polymers with pendant iodine-containing groups are described, for example, in International Publication Nos. WO 2011 / 110589, WO 2020003147, WO 2020 / 003153, and U.S. Patent Application Publication No. 2021 / 0015963, which are incorporated herein by reference.

[0051] In certain embodiments, the polymer is a polymer comprising a PVA backbone with pendant monoiodine, diiodine, triiodine or tetraiodine phenyl groups, or a combination of one or more such groups, particularly those linked via cyclic acetal groups. Such polymers are described in International Publication No. 2020 / 003153 (the entirety of which is incorporated herein by reference). In one such polymer, the PVA comprises a group of the following formula I:

[0052] [ka]

[0053] In more specific embodiments, the polymer comprises a PVA backbone having a first pendant group and a second pendant group, the first pendant group being a mono-, di-, tri-, or tetra-iodophenyl group attached to the PVA backbone via a cyclic acetal, e.g., as described above, and the second pendant group being a sulfonated phenyl group attached to the PVA backbone via a cyclic acetal. An example of such a group is shown in Formula II. The sulfonic acid group may be in the form of a salt, such as a sodium salt.

[0054] [ka]

[0055] Such polymers are described in WO 2021 / 009734, which is incorporated herein by reference in its entirety. In certain embodiments, the polymer of the precipitable liquid composition is an iodinated PVA polymer in which the PVA backbone comprises a group of Formula I and a group of Formula II. In some particular embodiments, the solvent is DMSO. In some particular embodiments, the precipitable liquid composition comprises 2-50% wt / wt, more typically 3-25% wt / wt, of the iodinated polymer dissolved in the solvent.

[0056] The radiopacity of a polymer or macromer can be varied by adjusting the amount of iodine in the polymer. This can be achieved by varying the number of iodine atoms on the pendant groups or by varying the number of iodine-containing pendant groups in the polymer or macromer. The iodine content can be referenced based on the dry weight of the polymer or macromer. Radiopaque polymers or macromers for use herein can advantageously contain at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% wt / wt iodine by dry weight of the polymer or macromer. The iodine content can also be referenced by volume of the liquid composition. In some embodiments, the iodine content is determined based on the amount of iodine per cm 3 At least 10 mg iodine per cm, at least 25 mg / cm 3 of iodine, at least 50 mg / cm 3 of iodine, or at least 100 mg / cm 3 It may be beneficial to include iodine.

[0057] In some embodiments, the liquid compositions and solidified compositions described herein may include one or more therapeutic agents (e.g., when the liquid composition is used to form a drug depot or drug-releasing coating).

[0058] In some embodiments, the liquid and solidified compositions described herein may contain charged and / or uncharged therapeutic agents at physiological pH. Charged therapeutic agents may be electrostatically held within the solidified composition and subsequently released therefrom by ion exchange mechanisms (e.g., polymers and / or macromers in the solidified liquid composition may be, among other things, -COO - , SO3 - , -OPO3 2- , or -NH3 +(When the solidified composition contains charged groups such as carboxyl groups.) Charged therapeutic agents electrostatically held in the solidified composition may be eluted from the solidified composition in an electrolyte medium such as saline (0.90% w / v NaCl) or in vivo, e.g., in blood or tissue, resulting in sustained release of the therapeutic agent over hours, days, or even weeks. Uncharged therapeutic agents in the solidified composition may also be eluted from the solidified composition in vivo. This may be particularly advantageous, for example, when a rapid elution or "burst effect" is desired to rapidly deliver the therapeutic agent to tissue, or when the low solubility of the therapeutic agent under physiological conditions (rather than ionic interactions) determines the release profile.

[0059] In some embodiments, the liquid compositions and solidified compositions of any of the foregoing embodiments may contain one or more therapeutic agents in a range of 0.01 mg / ml or less to 10 mg / ml or more, e.g., 0.01 mg / ml to 0.025 mg / ml to 0.05 mg / ml to 0.10 mg / ml to 0.25 mg / ml to 0.5 mg / ml to 1 mg / ml to 2.5 mg / ml to 5 mg / ml to 10 mg / ml.

[0060] Examples of therapeutic agents (which may also be referred to herein as pharmaceutically active ingredients) that can be incorporated into the liquid and solidified compositions of any of the foregoing embodiments include small molecule therapeutic agents (defined herein as therapeutic agents having a molecular weight of 2000 g / mol or less, typically less than 1500 g / mol, and more typically less than 1000 g / mol), and biomolecules (e.g., polypeptides, including proteins and protein fragments, such as antibodies and antibody fragments and oligopeptides, and polynucleotides and oligonucleotides, including nucleic acids and nucleic acid analogs, such as deoxyribonucleic acid, ribonucleic acid, peptide nucleic acid, and fragments thereof).

[0061] Examples of therapeutic agents include anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T cell agonists, and STING (stimulator of interferon genes) agonists, among others.

[0062] Examples of therapeutic agents include, among others, checkpoint inhibitors including inhibitors of binding of PD-1 to PD-L1, inhibitors of binding of CTLA-4 to CD80 and / or CD86, inhibitors of binding of TIGIT to CD-112, and inhibitors of binding of LAG-3 to MHC class II molecules; antibodies or antigen-binding fragments thereof that bind to: PD-1 (e.g., pembrolizumab, nivolumab, domvanalimab, etc.), PD-L1 (e.g., atezolizumab, avelumab, durvalumab, etc.), LAG-3 (e.g., levothyroxine ... latolimab, etc.), TIM-3 (e.g., LY3321367, MBG453, TSR-022, etc.), TIGIT (e.g., etigilimab, tiragolumab, vibostolimab, etc.), or CTLA-4 (e.g., ipilimumab, tremelimumab, etc.); CD3, CD19, CD20, CD22, CD52, CD79B, CD30, CD33, CD38, CD52, CD79B, HER2, EGFR, VEGF, VEGFR2, EPCAM / CD3, GD2, IL-6, RANKL, SLAMF7, CCR4 , PDGFRα, nectin-4, or TROP2; immunomodulatory cytokines such as IL-2, IL-12, IL-15, IL-23, interferon gamma (IFN-γ), and gm-CSF (granulocyte-macrophage colony-stimulating factor); T cell agonists, for example, TLR3 agonists (e.g., polyinosinic acid:polycytidylic acid, double-stranded RNA, etc.), TLR7 agonists (e.g., TMX-202, gardiquimod, imiquimod, etc.), and TLR8 agonists. (e.g., VTX-2337, etc.), TLR7 / 8 agonists (e.g., MEDI9197, R848, resiquimod, etc.), TLR9 agonists (e.g., lefitolimod (MGN1703), tilsotolimod, CpG oligodeoxynucleotides (e.g., agatolimod), etc.); and STING agonists, such as GSK532, cyclic dinucleotides (e.g., cyclic guanosine monophosphate-adenosine monophosphate), CRD5500 (LB-061), E7766, ADU-S100, SB11285 MSA2, MK1454, TTI-10001, etc.).

[0063] Further exemplary therapeutic agents include camptothecins (such as irinotecan and topotecan) and anthracidines (such as doxorubicin, daunorubicin, idarubicin, and epirubicin), antiangiogenic agents (such as axitinib, bortezomib, bosutinib, canertinib, dovitinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, mastinib, Vascular endothelial growth factor receptor (VEGFR) inhibitors (such as muvitinib, pazopanib, semaxanib, sorafenib, sunitinib, tandutinib, vandetanib, vatalanib, and vismodegib), microtubule assembly inhibitors (such as vinblastine, vinorelbine, and vincristine), aromatase inhibitors (such as anastrazole), platinum-based agents (cisplatin, oxaliplatin, and oxaliplatin), and saliplatin, carboplatin, and miriplatin), nucleoside analogs (such as 5-FU, cytarabine, fludarabine, and gemcitabine), paclitaxel, docetaxel, mitomycin, mitoxantrone, bleomycin, pingyangmycin, abiraterone, amifostine, buserelin, degarelix, folinic acid, goserelin, lanreotide, lenalidomide, letrozole, leuprolide, octreotide, tamoxifen, triptorelin, bendamustine, chlorambucil, dacarbazine, melphalan, procarbazine, temozolomide, rapamycin (and analogs such as zotarolimus, everolimus, umirolimus, and sirolimus), methotrexate, pemetrexed, or raltitrexed.

[0064] In some embodiments, the liquid and solidified compositions of any of the foregoing embodiments may further comprise a therapeutic and / or imageable radioisotope. Liquid and solidified compositions containing a therapeutic radioisotope can be used, for example, for brachytherapy, such as selective internal radiation therapy (SIRT) or cancer treatment, and can be delivered by any of the methods described elsewhere herein in connection with other embodiments. In one approach, the radioisotope can be attached via ionic interactions or covalently attached via a carrier, such as a chelating agent. In some embodiments, the radioisotope can be in the form of particles incorporated into the liquid and solidified compositions, the particles comprising the radioisotope. Such particles can be in the form of microspheres, typically having a maximum diameter in the range of 5 μm to 500 μm, particularly less than 100 μm. The particles can be, for example, polymeric or ceramic. One such ceramic is yttrium aluminosilicate ceramic (see, for example, U.S. Pat. No. 4,789,501). Further examples of ceramic microspheres are described in WO 16082045 and WO 05087274. Therapeutic radioisotopes include, but are not limited to: 177 Lu, 90 Y, 131 I, 89 Sr, 153 Sm, 223 Ra, 224 Ra, 211 At, 225 Ac, 227 Th, 212 Bi, 213 Bi, and / or 212 In some embodiments, the therapeutic radioisotope is 177 Lu, 90 Y, 131 I, 89 Sr, 153 Sm, and / or 223 In some embodiments, the therapeutic radioisotope is one or more of 90 Y. Imagable radioisotopes include, but are not limited to: 99m Tc,201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K. 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr and 177 In some embodiments, the imageable isotope is 99m Tc, 67 Ga, 68 Ga, 64 Cu or 89 In some embodiments, the imageable isotope is Zr. 99m In some embodiments, the imageable isotope is Tc. 89 It is Zr.

[0065] Other embodiments of the present disclosure relate to medical compositions corresponding to or formed from the liquid compositions of any of the preceding embodiments. For example, as previously described, such liquid compositions can be used to form emboli, fiducial markers, tissue barriers, therapeutic agent depots, and coatings for medical devices.

[0066] Still other embodiments of the present disclosure relate to medical procedures using the liquid compositions described herein. For example, in some embodiments, the medical procedure is a method of tissue embolization, which includes delivering the liquid composition into one or more blood vessels that nourish the tissue. Such procedures can be used to treat a variety of conditions, including arteriovenous malformations, gastrointestinal bleeding, aneurysm filling, and solid tumors, particularly hypervascular tumors of the liver, prostate, kidney, brain, colon, bone, lung, etc., as well as benign hyperplastic conditions such as benign prostatic hyperplasia and uterine fibroids.

[0067] In some embodiments, the medical treatment is a local or systemic therapeutic agent delivery method comprising delivering to a patient (e.g., onto, into, between the patient's tissues, etc.) a liquid composition described herein (e.g., by injection, spraying, etc.).

[0068] In some embodiments, the medical procedure is a therapeutic method comprising delivering (e.g., by injection, spraying, etc.) a liquid composition described herein into or onto a tumor of a patient, whereby the therapeutic agent is released into the tumor.

[0069] In some embodiments, the medical procedure is a method of separating a first tissue from a second tissue, comprising delivering (e.g., injecting, etc.) a liquid composition described herein between the first tissue and the second tissue (e.g., between prostate tissue and rectal tissue).

[0070] In still further embodiments, the present disclosure relates to the use of the liquid compositions described herein in the manufacture of medicaments for the treatment of various diseases and conditions, including the treatment of arteriovenous malformations, the treatment of gastrointestinal bleeding, the filling of aneurysms, the treatment of solid tumors, particularly hypervascular tumors of the liver, prostate, kidney, brain, colon, bone, lung, and the like, and the treatment of benign hyperplastic conditions such as prostatic hyperplasia and uterine fibroids.

[0071] The present disclosure also relates to the use of any of the therapeutic agents described herein in the manufacture of a medicament for the treatment of such diseases and conditions, wherein the therapeutic agent is incorporated into a liquid or solidified composition described herein. The present disclosure also relates to the use of any of the therapeutic agents described herein in the treatment of such diseases and conditions, wherein the therapeutic agent is incorporated into a liquid or solidified composition described herein. Liquid compositions may be particularly useful when the liquid composition is delivered, for example, via a catheter route, by injection, by implantation, or by spray.

[0072] Example 1: Synthesis of iodinated PVA polymer Iodinated PVA polymer was prepared according to Example 13 of WO 2021 / 009734. Briefly, a dry 600 ml HEL Ltd PolyBLOCK™ vessel was fitted with a nitrogen blanket. Dry DMSO (120 ml, 40.2 volumes) was added with stirring at 500 rpm, followed by PVA (146-189 kDa, 99% hydrolyzed, 5.0 g). The suspension was heated to 50 °C until all solids were completely dissolved. 1,3,5-triiodobenzaldehyde (TIBA) was then added (10.4 g, 0.4 equivalents relative to the PVA-1,3-diol units), followed by 0.05 equivalents of 2-sulfobenzaldehyde sodium salt (Sigma Aldrich UK) (F-SAS). After complete dissolution, methanesulfonic acid (11 ml, 3.37 vol) in approximately 20 mL of cold DMSO was added and stirring was continued overnight at 50° C. The pale yellow solution was cooled to room temperature and precipitated by the slow addition of acetonitrile (250 mL).

[0073] The yellow supernatant was removed by vacuum, and the resulting white polymer was redissolved in DMSO (approximately 100 mL) at 50 °C and reprecipitated with acetonitrile. Excess solvent was removed by vacuum. The white polymer was suspended in 0.1 N NaOH (100 mL) for 20 min and then mixed to achieve a uniform suspension. After removing excess solvent, it was neutralized to pH = 7 with deionized water (100 mL x 3). After removing excess water by vacuum, the resulting white polymer was suspended in acetone (100 mL x 3), and the solid was isolated by filtration using a Buchner funnel. The solid was then dried overnight in a vacuum oven at 28-32 °C to obtain the desired product (white solid, 11-13.0 g, yield approximately 75-80% w / w).

[0074] Example 2: General preparation of liquid embolic prototype Sample prototypes were prepared by dissolving iodinated PVA, prepared according to the general synthesis protocol above, in DMSO. The vial containing the thick suspension was then sealed and sonicated until complete dissolution (typically about 4 hours).

[0075] Example 3: General preparation of tantalum suspension Tantalum powder was suspended in the iodized PVA formulation by vortexing at 2800 rpm for 20 minutes. The suspension prepared using spherical tantalum powder exhibited a more visually stable particle distribution compared to the suspension prepared using non-spherical tantalum. The following tantalum formulations were obtained:

[0076] [Table 1]

[0077] Example 4: Comparison of the rheological properties of spherical, agglomerated, and milled tantalum preparations. Liquid embolic formulations were prepared according to Examples 1-3. The formulations contained spherical or agglomerated Ta powder. Their rheological properties were compared using an Anton Paar MCR 302 rheometer (Anton Paar, St. Albans, UK) with the following settings: cone-plate setup;

[0078] Setup: Corn plate Cone shape: 60mm (diameter), 1° angle Cone-plate gap at measurement position: 0.122 mm Temperature range: 19℃~40℃ Heating rate: 2℃ / min Shear rate: 50 s -1 The spherical powder formulations consistently have lower viscosities than the agglomerated powder formulations at a given tantalum powder concentration (Table 2).

[0079] [Table 2]

[0080] A liquid embolic polymer was prepared using PVA with a molecular weight of 146-189 kD containing 0.4 equivalents of TIBA and 0.075 equivalents of FSAS. The polymer was dissolved in DMSO to give a final concentration of 7% w / w (in the final ternary mixture).

[0081] Example 5: Mechanical testing The polymer from Example 4 was redissolved in DMSO to a final concentration of 7% w / w. Tantalum samples (spherical, aggregated, or crushed) were incorporated to achieve final concentrations of 20% w / w or 35% w / w. Mechanical testing specimens were prepared by extruding the liquid embolic formulation through a 20 μl cylindrical glass micropipette (Drummond, Broomall, PA, USA) into phosphate-buffered saline (pH 7.0; 37°C; PBS) at a constant injection rate of approximately 0.4 ml / min (25 mm / min). This was accomplished by attaching the pipette to the end of a Metcal dispenser tip (OK International; Cypress, CA, USA 90630) and delivering the solution using an appropriate syringe driver. The glass pipette tip was maintained in contact with the PBS. The as-formed polymer strings had a cylindrical shape with a regular cross-section of approximately 600 μm in diameter. The length varied depending on the total volume injected. Samples were stored overnight in deionized water and were tested and used as soon as possible after removal from the storage solution to prevent drying.

[0082] For each sample, the formed string was characterized by optical microscopy to confirm its regular cylindrical shape. The diameter and length were recorded. The wet ends of the string were then clamped in the tensile test grips of a Lloyd (AMETEK) universal testing machine (LF Plus LF1243, PN01471), and the string was pulled to measure its mechanical properties under tensile load. The following test conditions were used: a 500 N load cell set to stop at 300 N; initial specimen length: approximately 35 mm; crosshead speed: 60 mm / min (constant); specimen cross-section: approximately 600 μm.

[0083] The string tensile tests showed that spherical Ta significantly improved the mechanical performance of the formed solid emboli, with the elongation at break increasing from 100% (aggregate A) to 300% (spherical) and the ultimate tensile strength increasing from 0.28 MPa (aggregate A) to 0.43 MPa (spherical).

[0084] Figure 1A is an image showing the string in the tensile test setup, and Figure 1B is an image showing the uniform distribution of spherical Ta particles at a microscopic level. Figure 2A is a microscopic image of a string without Ta particles (the tensile test setup is shown in the inset). Figure 2B is another microscopic image of a string with spherical Ta particles. Figure 2C is a microscopic image of a string with agglomerated Ta particles. The spherical Ta preparation was the only one that strongly favored a uniform distribution of Ta particles throughout the preparation, i.e., within the solid strings formed. Strings obtained from preparations containing agglomerated Ta showed a very non-uniform distribution of particles, with frequent formation of agglomerates of Ta particles.

[0085] Example 6: Imaging Samples of the polymer thread prepared in Example 5 were suspended in 1% agarose gel (Sigma-Aldrich, UK) in Nunc cryotube vials (Sigma-Aldrich V7634, 48 mm x 12.5 mm). These "bead phantoms" were imaged using a micro-computed tomography (μCT) system (Bruker Skyscan 1172) at RSSL Laboratories, Reading, Berkshire, UK. Samples were reconstructed using NRecon software and calibrated against a region of interest (VOI) of purified water. Values ​​were reported in Hounsfield units and grayscale. Typical reconstructed cross sections are shown in Figures 3A-3B, along with grayscale and Hounsfield values ​​for the same samples. X-ray shadowgraphs of the same preparations are shown in Figures 4A-4B.

Claims

1. A medical liquid composition comprising: (a) a polymer, a monomer, a macromonomer, or a combination of any two or all three thereof; and (b) spherical metal particles, said liquid composition containing 0.1 to 0.9 g / ml of said spherical metal particles, said liquid composition being a sterile injectable liquid composition that solidifies in situ upon injection into a subject; A liquid composition wherein at least a portion of said polymers comprise pendant iodine-containing groups and / or at least a portion of said macromonomers comprise pendant iodine-containing groups.

2. 2. The liquid composition of claim 1, wherein the spherical metal particles are selected from tantalum, tungsten, rhenium, niobium, molybdenum, and alloys thereof.

3. 10. The liquid composition of claim 1, wherein the spherical metal particles have one, two, or all three of the following characteristics: (a) an average aspect ratio in the range of 1.0 to 1.25; (b) D10 and D90 values ​​within 50% of the median diameter; and (c) a median particle size in the range of 1 to 10 μm.

4. The liquid composition of claim 1 , wherein the liquid composition is provided in a syringe.

5. 2. The liquid composition of claim 1, wherein the liquid composition is a polymerizable liquid composition comprising the spherical metal particles, the monomer and / or the macromonomer, and optionally a carrier solution, wherein the monomer and / or the macromonomer polymerizes upon contact with a polymerization initiator.

6. 10. The liquid composition of claim 1, wherein the liquid composition is a precipitating liquid composition comprising the spherical metal particles, the polymer, and a carrier solvent comprising a water-miscible organic solvent in which the polymer is dissolved.

7. 10. The liquid composition of claim 1, wherein the liquid composition is a gelled liquid composition comprising the spherical metal particles, the polymer, and a carrier solvent comprising an aqueous or water-miscible organic solvent in which the polymer is dissolved.

8. The liquid composition of any one of claims 1 to 7, wherein at least a portion of the polymer comprises a vinyl alcohol homopolymer or copolymer.

9. The liquid composition of any one of claims 1 to 7, wherein at least a portion of the polymer comprises a polysaccharide.

10. The liquid composition of any one of claims 1 to 5, wherein at least a portion of the macromonomer comprises a vinyl alcohol homopolymer or copolymer.

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