Rare-earth phosphate compositions and methods of use

Abstract

Provided herein are compositions for use in forming temporary occlusion of a target site and methods of making same. The compositions disclosed herein include rare-earth phosphates compositions for temporary occlusion of a target sites. The compositions can be used in a variety of medical indications, such as trauma, ambulatory transport, to prevent and / or control bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm, etc.).

Description

RARE-EARTH PHOSPHATE COMPOSITIONS AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 625,519 filed January 26, 2024, the entirety of which is incorporated herein by reference.TECHNICAL FIELD

[0002] The present disclosure generally relates to compositions for temporary occlusion of a target site and methods of making and using the same and, more particularly, to rare-earth phosphates compositions for temporary occlusion of a target sites.BACKGROUND

[0003] During medical interventions, there is often a need to temporarily occlude normally functioning body lumens to redirect fluid flow. However, the majority of interventions, including ethanol injections, coils, and adhesive glues result in permanent embolization of the lumen. Temporary occlusions or stasis of fluid flow through the lumen may be more beneficial in some situations such as trauma or hemorrhage. However, removing a temporary occlusive device requires special procedures and tools. Of the occlusive gels and liquids that degrade after administration, the compositions that are available take days or weeks to degrade. Additionally, enzymatic degradation of the temporary occlusion varies between subjects because of differences in enzyme expression and the amount of occlusive material injected to the subject.

[0004] Accordingly, a need exists to develop new compositions that temporarily occlude body lumens that enable greater flexibility in restoring fluid flow quickly.SUMMARY

[0005] The present disclosure is directed to compositions for creating a transient occlusion of a target site in a subject for a variety of medical indications, such as controlling bleeding.

[0006] In one embodiment, the present disclosure is directed to a method of controlling bleeding in a subject in need thereof by administering a composition comprising a rare-earth phosphate to a target site within the subject, wherein the rare-earth phosphate has a xenotimecrystal structure. The composition forms an occlusion at the target site, and the occlusion substantially occludes fluid flow at the target site for a duration of time of less than 120 minutes.

[0007] Another embodiment of the present disclosure relates to a method of stating fluid flow in a subject in need thereof by administering a composition comprising a rare-earth phosphate to a target site within the subject, wherein the composition forms a penetrable occlusion, and the penetrable occlusion substantially occludes fluid flow at the target site for a duration of time less than 120 minutes; and inserting a medical device through the penetrable occlusion, wherein inserting the medical device does not reestablish fluid flow at the target site.

[0008] Additional features and advantages of the embodiments described herein will be set forth in the detailed description that follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments described herein, including the detailed description that follows, the claims, as well as the appended drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 depicts photographs of a swine liver before and after injection with yttrium phosphate, demonstrating occlusion of the distal vascular bed.

[0010] FIG. 2 depicts photographs of the splenic artery before and after injection with yttrium phosphate.

[0011] FIG. 3 depicts photographs of a swine kidney before and after injection with yttrium phosphate.

[0012] FIG. 4 depicts a photograph of a swine liver after injection with yttrium phosphate, with the microcatheter tracked past the injection site, through the occlusion.DETAILED DESCRIPTION

[0013] Features and advantages of the present disclosure will now be described with occasional reference to specific embodiments. However, the disclosure may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, theseembodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the present disclosure to those skilled in the art.

[0014] Embodiments of the present disclosure relate to compositions for creating a transient occlusion of a target site in a subject. Particular embodiments of the disclosure relate to compositions for creating a transient occlusion of a target site in a subj ect without impeding device access. In embodiments, the target site is any anatomical site in a subject wherein fluid flows. Illustrative target sites include, but are not limited to body lumens, such as blood vessels, aneurysmal sacs, fallopian tubes, uterine lumina, renal tubules, urethra, intestines, ducts; wounds; perforations; diseased tissues, such as tumors.

[0015] While the following terms are believed to be well understood by one of ordinary skill in the art, definitions are set forth to facilitate explanation of the presently-disclosed subject matter.

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently- disclosed subject matter belongs.

[0017] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently- disclosed subject matter.

[0018] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

[0019] It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitationswere expressly writen herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0020] The term “subject” as used herein refers to any living organism to which a pharmaceutical can be administered. The term subject includes, but is not limited to, humans, nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats, guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult, child, and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.

[0021] Embodiments of the present disclosure generally include compositions for use and methods of temporarily occluding fluid flow within a subject by administering a composition comprising rare-earth phosphate particles to a target site within the subject, wherein the composition forms an occlusion, and the occlusion substantially occludes fluid flow at the target site for a duration of time less than 120 minutes.

[0022] Embodiments of the present disclosure generally include compositions having one or more rare-earth phosphates. The terms “rare-earth,” “rare-earth metals,” and / or “rare-earth elements” as used herein refer to one or more of yttrium, scandium, lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium erbium, thulium, ytterbium, and lutetium. It will also be appreciated by those in the art that lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium are known as lanthanides. The rare-earth atom of the rare-earth phosphate may be any known isotope of the rare-earth atom and may be non-radioactive, such as89Y, or radioactive, such as90Y.

[0023] The term “phosphates” as used herein refers to salts comprising one or more of: a phosphate (orthophosphate) ion (PC3-), a hydrogen phosphate ion (HPC2-), a dihydrogen phosphate ion (H2PO4-), a pyrophosphate ion (P2O?4-), a triphosphate ion (PsOio5-), a tetraphosphate ion (P4O136-), etc.

[0024] Rare-earth phosphates may also encompass compounds having two, three, four, or more than four different rare-earth cations. For example, rare-earth compounds may include mixed- metal phosphates of formula (M1)X(M2)I-XPO4, where M1and M2are different rare-earth metals, and x is greater than zero and less than one. Rare-earth compounds may include mixed-metal phosphates of formula (M1)x(M2)y(M3)i-x-yPO4, where M1, M2, and M3are each different rare- earth metals, and x and y are independently greater than zero and less than one. Rare-earth compounds further include mixed-metal phosphates of formula (M1)x(M2)y(M3)z(M4)i-x-y-zPO4, where M1, M2, M3, and M4are each different rare-earth metals, and x, y, and z are independently greater than zero and less than one.

[0025] In some embodiments, the composition includes one or more rare-earth phosphates having a xenotime crystal structure, a monazite crystal structure, a rhabdophane crystal structure, and / or a churchite crystal structure, or combinations thereof. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure and a monazite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure and a rhabdophane crystal structure. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure and a churchite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a monazite crystal structure and a rhabdophane crystal structure. In some embodiments, the composition includes rare-earth phosphates having a monazite crystal structure and a churchite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a rhabdophane crystal structure and a churchite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure, a monazite crystal structure and a rhabdophane crystal structure. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure, a monazite crystal structure and a churchite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a monazite crystal structure, a rhabdophane crystal structure, and a churchite crystal structure. In some embodiments, the composition includes rare-earth phosphates having a xenotime crystal structure, a monazite crystal structure, a rhabdophane crystal structure, and a churchite crystal structure.

[0026] In some embodiments, the composition includes one or more rare-earth phosphates having a xenotime crystal structure. A “xenotime crystal structure” refers to the ditetragonal dipyramidal point group of the tetragonal crystal system of crystallographic space group ofI4i / amd. It will be appreciated that rare-earth phosphates having a xenotime crystal structure feature a network of tetrahedral phosphate ions (PC3-) and rare earth ions in distorted 8-fold coordination. Non-limiting examples of rare-earth phosphates having a xenotime crystal structure include YPO4, ErPC , DyPC , HoPO4, TmPC , YbPC , and LuPC

[0027] In some embodiments, the composition includes one or more rare-earth phosphates having a monazite crystal structure. A “monazite crystal structure” refers to the prismatic point group of the monoclinic crystal system having space group P2i / n. It will be appreciated that the structure of monazite are characterized by alternating rare earth ions and phosphate tetrahedra. Non-limiting examples of rare-earth phosphates having a monazite crystal structure include CePO4, LaPC , PrPO4, NdPO4, SmPO4, and GdPO4.

[0028] In some embodiments, the composition includes one or more rare-earth phosphates having a rhabdophane crystal structure. A “rhabdophane crystal structure” refers to either the hexagonal trapezohedral point group of the hexagonal crystal system having space group P6222 or the sphenoidal point group of the monoclinic crystal system, having space group C2. It will be appreciated that the rhabdophane structure may form in hydrated states ( 1H2O) with n optionally ranging from 0.5 to 1. Optionally, the phosphate ion in the rare-earth phosphate having a rhabdophane crystal structure is an orthophosphate. Non-limiting examples of rare-earth phosphates having a rhabdophane crystal structure include CePO4, LaPO4, PrPO4, NdPO4, and SmPO4.

[0029] In some embodiments, the composition includes one or more rare-earth phosphates having a churchite crystal structure. A “churchite crystal structure” as used herein refers to the prismatic point group of the monoclinic crystal system, particularly those having space group C2 / c. It will be appreciated that the churchite structure may form in hydrated states with general formula of REPO4’2H2O. Non-limiting examples of rare-earth phosphates having a churchite crystal structure include CePC , YtPC , LaPCU, NdPCU, SmPCU and GdPC .

[0030] In embodiments, the rare-earth phosphates are formed by reacting one or more rare- earth halides (e.g., chlorides, bromides, or iodides of the rare-earth metals), with one or more phosphate salts to generate rare-earth phosphate particles. In some embodiments, the rare-earth halide is mixed with a solution containing one or more phosphates, such as phosphate-buffered saline. Optionally, this occurs in the presence of a dilute acid. In some embodiments, the rare-earth phosphate particles precipitate out of the solution. It will be appreciated that the reaction conditions, such as temperature, pH, concentration of the reactants, and reaction time, may be adjusted to control the size, morphology, and crystallinity of the resulting rare-earth phosphate particles.

[0031] In embodiments, the precipitated rare-earth phosphate forms particles. Individual rare- earth phosphate particles may have diameters of about 50 nanometers (nm) to about 1500 nm, including about 50 nm, about 100 nm, about 200 nm, about 250 nm, about 300 nm, about 400 nm, about 500 nm, about 600 nm, about 700 nm, about 750 nm, about 800 nm, about 900 nm, about 1000 nm, about 1100 nm, about 1200 nm, about 1250 nm, about 1300 nm, about 1400 nm, and about 1500 nm, including any subrange defined by any two of the aforementioned values.. In other embodiments, the particles may have diameters of about 50 nm to about 1000 nm, about 50 nm to about 500 nm, about 100 nm to about 1500 nm, about 100 nm to about 1000 nm, about 100 nm to about 500 nm, about 500 nm to about 1500 nm, about 500 nm to about 1000 nm, or about 1000 nm to about 1500 nm.

[0032] Yttrium phosphate nanocrystals predominantly find their utilization in the realm of light-emitting diode (LED) technologies. Conventional processing techniques require substantial pH changes to adjust the crystal structure and extremely elevated temperatures (approximately 800° C) to obtain pure crystalline material.

[0033] However, embodiments of the present disclosure form the rare-earth phosphates using a pressure vessel that enables heating, mixing, and pressure to form pure, rate-earth phosphate nanoparticles at much lower temperatures than conventional methods. Exemplary processing temperatures used in the presently disclosed methods range from about 10° C to about 180° C, including about 15° C, about 20° C, about 25° C, about 30° C, about 35° C, about 40° C, about 45° C, about 50° C, about 55° C, about 60° C, about 65° C, about 70° C, about 75° C, about 80° C, about 85° C, about 90° C, about 95° C, about 100° C, about 105° C, about 110° C, about 115° C, about 120° C, about 125° C, about 130° C, about 135° C, about 140° C, about 145° C, about 150° C, about 155° C, about 160° C, about 165° C, about 165° C, about 170° C, about 175° C, including any range having endpoints defined by any two of the aforementioned values.

[0034] Optionally, the rare-earth phosphate particles are sterilized after formation. Illustrative, non-limiting examples of suitable sterilization techniques include steam sterilization, dry heatsterilization, filtration, radiation sterilization, etc. Optionally, the rare-earth phosphate particles are steam sterilized at a temperature of from about 121° C to about 134° C. In some embodiments, the rare-earth phosphate particles are sterilized for a period of time of from about 5 minutes to about 45 minutes. In some embodiments, the rare-earth phosphate particles are steam-sterilized at about 121° C for about 30 minutes.

[0035] In embodiments, the rare-earth phosphate particles can be stored and / or transported in a storage solution. In some embodiments, the storage solution contains phosphate. Exemplary storage solutions include phosphate-buffered saline (PBS), Sorensen’s phosphate buffer, potassium phosphate buffer (Gomori buffer), citrate -phosphate buffer, and the like. Any suitable phosphate containing solution is contemplated and possible.

[0036] The rare-earth phosphate particles may be provided in such a form that a clinician needs to add only a pharmaceutically acceptable aqueous solution such as water or saline solution (e.g., 0.9% saline) to the rare-earth phosphate particles to prepare the particles for use in a medical procedure. As used herein, the term “pharmaceutically acceptable” refers to those solutions approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. Additional, non-limiting, suitable solutions for preparing the phosphate particles for use in a medical procedure include Lactated Ringers, Ringers acetate, D5W, and D5NS, though other solutions are contemplated and possible.

[0037] In embodiments, the rare-earth phosphate particles are suspended in the aqueous solution for injection. In some embodiments, the rare-earth phosphate particles are suspended in the aqueous solution in an amount ranging from about 0.050 mg to about 0.900 mg, including about 0.075 mg, 0.100 mg, 0.125 mg, 0.150 mg, 0.175 mg, 0.200 mg, 0.225 mg, 0.250 mg, 0.275 mg, 0.300 mg, 0.325 mg, 0.350 mg, 0.375 mg, 0.400 mg, 0.425 mg, 0.450 mg, 0.475 mg, 0.500 mg, 0.525 mg, 0.550 mg, 0.575 mg, 0.600 mg, 0.625 mg, 0.650 mg, 0.675 mg, 0.700 mg, 0.725 mg, 0.750 mg, 0.775 mg, 0.800 mg, 0.825 mg, 0.850 mg, and 0.875 mg or any range having endpoints defined by any of the aforementioned values. In some embodiments, the rare-earth phosphate particles are suspended in the aqueous solution in an amount ranging from about 0.125 mg to about 0.625 mg. some embodiments, the rare-earth phosphate particles are suspended in the aqueous solution in an amount ranging from about 0.300 mg to about 0.600 mg. In some embodiments, 0.375 mg of rare-earth phosphate particles are suspended in the aqueous solution.

[0038] The compositions may further include one or more imaging agents to use in connection with diagnostic imaging or therapeutic procedures. As used herein the term “imaging agent,” refers to any chemical or compound that is capable of producing a detectable signal itself or upon exposure to an external source of energy. In embodiments, the imaging agent may be an imaging agent adapted for use in magnetic resonance imaging (MRI) or functional MRI, magnetic particle imaging (MPI), an intravenous CT contrast agent, a radiopharmaceutical PET or single photon emission computed tomography (SPECT) tracer, an ultrasound contrast agent, an optical contrast agent, a myocardial perfusion tracer, a cerebral perfusion tracer and the like. Illustrative, nonlimiting examples of imaging agents include compounds containing radioisotopes, fluorochromes, gadolinium, iodine, barium, microbubbles, iron-oxide nanoparticles, and the like.

[0039] In an exemplary method of using the compositions described herein, the composition, when administered to a subject, temporarily occludes fluid flow at a target site. In some embodiments, the composition is administered at a target site to block fluid flow through a body lumen. For example, the compositions disclosed herein can be used to occlude a blood vessel to prevent and / or control bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm, etc.) or to ablate diseased tissue (e.g., tumors, etc.).

[0040] In embodiments, compositions of the present disclosure are administered to control fluid flow internally. In other embodiments, the compositions of the present disclosure are administered to control fluid externally, such as in the treatment of a wound. The term “administration” of the compositions defined herein includes systemic use, as by parenteral administration, (e.g., injection, intravenous infusion, etc.), suppositories, transdermal administration, nasal, bronchial, or respiratory administration, and oral administration thereof, as well as local administration of the compositions. In some embodiments, the composition is administered to a subject by injection of the composition at the target site within a body lumen.

[0041] The term “occlude,” “occlusion,” and grammatical equivalents thereof, as used herein refers to a process by which a composition is administered to the target treatment site for the purpose of at least partially obstructing fluid flow through the target site. A partially occluded fluid flow represents a reduction in values associated with a baseline or reference measurement in an un-occluded target site. It will be appreciated that the baseline measurement may be related to a normal physiological condition. Alternatively, the baseline measurement may be related to fluid flow outside the normal physiologic condition, such as in uncontrolled bleeding. In embodiments,the compositions substantially occlude fluid flow when administered by forming an occlusion at the target site. The term “substantially occlude” as used herein refers to a reduction of fluid flow (expressed in unit volume per unit of time) by about 80 percent or more compared to the baseline. In embodiments, the compositions substantially occlude the lumen by reducing fluid flow at the target site from about 80 percent to about 100 percent. In some embodiments, the compositions reduce the fluid flow at the target site by more than 95 percent. In other embodiments, the compositions reduce the fluid flow at the target site by more than 99 percent.

[0042] In embodiments, a temporary occlusion is formed at the target site when the composition is contacted by a fluid, thereby causing precipitation of the rare-earth phosphates at the target site. Exemplary fluids causing precipitation include, but are not limited to, blood, saliva, urine, sweat, tears, cerebrospinal fluid, synovial fluid, semen, breast milk, gastric acid, mucus, lymph, serous fluid and the like. When the composition precipitates at the target site, fluid flow is temporarily occluded.

[0043] In some embodiments, for example in a clinical setting, it may be desirable to selectively occlude a target site. For example, it may be desirable to reduce or minimize flow to prevent destabilization of a stent, coil, or longer lasting liquid embolic. In some embodiments, the compositions disclosed herein may be used to temporarily reduce fluid flow to allow more time for a permanent solution to be implemented, such as during a traumatic event or during ambulatory transport. In some embodiments, the compositions described herein are administered to control bleeding in a subject in need thereof. For example, and without being bound by theory, during treatment of a traumatic injury, occluding blood flow may prevent hemorrhagic shock, minimize blood loss, thereby preserving circulating blood volume and oxygen delivery, maintain blood pressure, reduce the risk of contamination, facilitate clot formation, and increase the time for medical intervention, thereby improving the chances of survival of the subject. Further, in embodiments, controlling bleeding may improve visibility for treatment. Severe bleeding may obscure an injury site, making it difficult for clinicians and / or first responders to assess and treat the wound.

[0044] Optionally, the compositions described herein may be used to prevent or inhibit nontargeted delivery of localized treatments, such as radioisotopes (e.g.,90Y) or localized vasodilator drugs. For example, in some embodiments, the target site for administration of the composition is in a first branch of the vasculature. The first branch may be occluded to allow application of atherapeutic agent or other localized treatment to a second branch of the vasculature. By temporarily halting blood flow in in the first branch, the therapeutic agent may be delivered to the intended site in the second branch, minimizing the risk of unintended distribution or side effects.

[0045] In some embodiments, the compositions form penetrable occlusions. As used herein, a “penetrable occlusion” refers to an occlusion formed by administering the composition to the target site and thereafter, penetrating, piercing, or otherwise inserting a medical device through the occlusion such that penetrating, piercing, or otherwise inserting the medical device does not disrupt the temporary occlusive effect. In embodiments, penetration of a medical device through the occlusion does not reestablish fluid flow in the lumen. Exemplary medical devices include catheters, microcatheters, microsyringes, and the like. By allowing access through the occlusion, a clinician can temporarily occlude fluid flow to a region while still accessing it to work more efficiently. It will be appreciated that a penetrable occlusion enables treatment of the lumen beyond the occlusion while maintaining reduced fluid flow. For example, administration of therapeutic agents, placement of devices such as stents, ablations, etc. may benefit by occluding fluid flow prior to treating the location. Further, occluding fluid flow may minimize the risk of downstream embolization.

[0046] In embodiments, the composition forms a self-sealing occlusion. As used herein “selfsealing occlusion” refers to an occlusion that, after insertion of a medical device through the occlusion, the occlusion reforms around the medical device, thereby preventing fluid flow at the target site. A self-sealing occlusion, in some embodiments, reforms when the medical device is removed from the occlusion.

[0047] In embodiments, the composition may be administered at a target site while the medical device remains in place. The occlusion forms around the medical device, enabling a clinician to infuse one or more additional therapeutics or insert additional medical devices to the target site as treatment requires.

[0048] The occlusions formed by the compositions described herein may occlude fluid flow at the target site for a duration of time before the occlusion is resorbed. In embodiments, the duration of time is less than 60 minutes. In embodiments, the duration of time is less than 45 minutes. In embodiments, the duration of time is less than 30 minutes. In embodiments, the duration of time is less than 15 minutes. In embodiments, the duration of time is less than 10 minutes. In someembodiments, the duration of time is from about 5 minutes to about 45 minutes, or any subrange thereof. In some embodiments, the duration of time is from about 5 minutes to about 30 minutes. In some embodiments, the duration of time is at least about 15 seconds. In embodiments, the duration of time is at least about 30 seconds. In embodiments, the duration of time is at least about 45 seconds. In embodiments, the duration of time is at least about 60 seconds. In embodiments, the duration of time is at least about 5 minutes. In embodiments, the duration of time is at least about 10 minutes. In embodiments, the duration of time is at least about 15 minutes. In embodiments, the duration of time is at least about 30 minutes.

[0049] In some embodiments, the duration of time is from about 5 minutes to about 45 minutes, including about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 minutes or any subrange having endpoints defined by any two of the aforementioned values. In some embodiments, the duration of time is from about 5 minutes to about 30 minutes.EXAMPLES

[0050] The following examples are given by way of illustration and are in no way intended to limit the scope of the present disclosure.

[0051] Example 1 : Rare-earth phosphates

[0052] The temporary occlusive effect of various phosphate particles was evaluated in vivo. 0.375 mg of prepared yttrium phosphate (YPO4), holmium phosphate (HoPC ), cerium phosphate (CePCU), lanthanum phosphate (LaPCU), and praseodymium phosphate (PrPCU) particles, stored in PBS, were fully suspended in 0.9% w / v saline solution prior to injection The particles had an average diameter of 1 micron. The YPO4 and HoPO4 had a xenotime crystal structure. The CePC and LaPCU and PrPCU had a monazite crystal structure. To ensure even particle distribution, the solution was agitated immediately before use. The solution was delivered to the target site using a standard microcatheter or base catheter.

[0053] Both of the compositions containing rare-earth phosphates with xenotime crystal structures demonstrated stasis at the target site, while the compositions containing rare-earth phosphates with monazite crystal structures did not.

[0054] It is important to note that none of the analyzed solutions were sterilized prior to testing. This may have influenced the growth and integrity of the crystal structures, particularly for the monazite samples. Thus, incomplete crystallization or contamination may have contributed to the lack of efficacy observed in monazite-based phosphates.

[0055] Example 2: Target location

[0056] In swine models, yttrium phosphate successfully occluded a variety of target regions, including a kidney, a lobe of the liver, and the entire liver. Specifically, vascular occlusion was demonstrated in major arteries, including the hepatic artery, gastroduodenal artery, and splenic artery. Reflux of the contrast medium during injection extended back past the microcatheter tip, providing visual confirmation of effective occlusion

[0057] Near-total occlusion was observed in these vessels upon injection of the phosphate solution, as shown in FIGS. 1-3. Resorption of the occlusion occurred and fluid-flow was reestablished after 15-30 minutes.

[0058] Example 3 : Penetrable Occlusion

[0059] To further assess the functionality of the occlusion, the yttrium phosphate solution was injected into the hepatic artery of a swine to occlude a specific liver lobe, as shown in FIG. 4. After injection, a microcatheter was advanced through the occluded vessel and contrast agent was introduced into the occluded lobe. Contrast medium injected beyond the occlusion point exhibited reflux down the hepatic arch rather than perfusing the liver vasculature, The results confirmed that the occlusion was maintained despite penetration by the microcatheter, demonstrating the stability and effectiveness of the rare earth phosphate particles in achieving temporary occlusion.

[0060] Aspects Fisting

[0061] In a first aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, optionally bleeding, in a subject in need thereof, the method comprising administering a composition comprising a rare-earth phosphate to a target site within the subject wherein the composition forms an occlusion at the target site, andthe occlusion substantially occludes fluid flow at the target site for a duration of time of less than 120 minutes.

[0062] In a second aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the rare-earth phosphate has a xenotime crystal structure, a monazite crystal structure, a rhabdophane crystal structure, a churchite crystal structure, or a combination thereof. Optionally, the rare-earth phosphate has a xenotime crystal structure.

[0063] In a third aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the rare-earth phosphate comprises yttrium phosphate, erbium phosphate, holmium phosphate, dysprosium phosphate, thulium phosphate, ytterbium phosphate, lutetium phosphate, terbium phosphate, or combinations thereof.

[0064] In a fourth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the rare-earth phosphate comprises yttrium phosphate.

[0065] In a fifth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the rare-earth phosphate comprises holmium phosphate.

[0066] In a sixth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein administering the composition comprises injecting the composition at the target site.

[0067] In a seventh aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the occlusion is penetrable by a medical device without reestablishing fluid flow through the lumen.

[0068] In an eighth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the duration of time is less than 90 minutes.

[0069] In a ninth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the duration of time is less than 60 minutes.

[0070] In a tenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the duration of time is less than 30 minutes.

[0071] In an eleventh aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, The method of claim 1, wherein the duration of time is from 15 minutes to 30 minutes.

[0072] In a twelfth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the composition further comprises a pharmaceutically acceptable solution.

[0073] In a thirteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the pharmaceutically acceptable solution is 0.9% saline.

[0074] In a fourteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the composition comprises from about 0.300 mg of rare-earth phosphate particles to about 0.600 mg of rare-earth phosphate particles.

[0075] In a fifteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the target site is a blood vessel.

[0076] In a sixteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the target site is a wound.

[0077] In a seventeenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the composition further comprises an imaging agent.

[0078] In an eighteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the bleeding is caused by trauma.

[0079] In a nineteenth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the bleeding is organ bleeding, gastrointestinal bleeding, vascular bleeding, or bleeding associated with an aneurysm.

[0080] In a twentieth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a composition for use in controlling bleeding, the composition comprising a rare-earth phosphate, wherein the rare-earth phosphate has a xenotime crystal structure, and wherein the rare-earth phosphate forms an occlusion that substantially occludes fluid flow at a target site in the subject for a duration of time of less than 120 minutes

[0081] In a twenty first aspect, alone or in combination with any other aspect herein, the present disclosure relates to a composition for use in controlling bleeding, wherein the rare-earth phosphate comprises yttrium phosphate, erbium phosphate, holmium phosphate, dysprosium phosphate, thulium phosphate, ytterbium phosphate, lutetium phosphate, terbium phosphate, or combinations thereof.

[0082] In a twenty second aspect, alone or in combination with any other aspect herein, the present disclosure relates to a composition for use in controlling bleeding, wherein the rare-earth phosphate comprises yttrium phosphate, holmium phosphate, or combinations thereof.

[0083] In a twenty third aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow in a subject in need thereof, the method comprising administering a composition comprising a rare-earth phosphate to a target site within the subject, wherein the composition forms a penetrable occlusion, and the penetrable occlusion substantially occludes fluid flow at the target site for a duration of time less than 120 minutes; and inserting a medical device through the penetrable occlusion, wherein inserting the medical device does not reestablish fluid flow at the target site.

[0084] In a twenty fourth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the medical device is a catheter, microcatheter, or microsyringe.

[0085] In a twenty fifth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow wherein the body lumen is a blood vessel.

[0086] In a twenty sixth aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein the composition further comprises an imaging agent.

[0087] In a twenty seventh aspect, alone or in combination with any other aspect herein, the present disclosure relates to a method of controlling fluid flow, wherein administering the composition comprises injecting the composition at the target site.

[0088] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that any particular order be inferred. Any recited single or multiple feature or aspect in any one claim can be combined or permuted with any other recited feature or aspect in any other claim or claims.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting.

[0090] As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms, including “at least one,” unless the content clearly indicates otherwise. “Or” means “and / or.” As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. It will be further understood that the terms “comprises” and / or “comprising,” or “includes” and / or “including” when used in this specification, specify thepresence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof. It is to be further understood that where descriptions of various embodiments use the term “comprising,” and / or “including” those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language “consisting essentially of’ or “consisting of.” The term “or a combination thereof’ means a combination including at least one of the foregoing elements.

[0091] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth as used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated, the numerical properties set forth in the specification and claims are approximations that may vary depending on the desired properties sought to be obtained in embodiments of the present disclosure. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. One of ordinary skill in the art will understand that any numerical values inherently contain certain errors attributable to the measurement techniques used to ascertain the values.

[0092] It should be understood that every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, examples include from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0093] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 25 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Withrespect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 25 may comprise 1 to 5, 1 to 10, 1 to 15, and 1 to 20 in one direction, or 25 to 20, 25 to 15, 25 to 10, and 25 to 5 in the other direction.

[0094] It is noted that the terms “substantially” and “about” may be utilized herein to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation. These terms are also utilized herein to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.

[0095] Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any embodiment disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests or discloses any such embodiment. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0096] While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the present disclosure. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this disclosure.

Claims

CLAIMS1. A method of controlling bleeding in a subject in need thereof, the method comprising: administering a composition comprising a rare-earth phosphate to a target site within the subject, wherein the rare-earth phosphate has a xenotime crystal structure, wherein: the composition forms an occlusion at the target site, and the occlusion substantially occludes fluid flow at the target site for a duration of time of less than 120 minutes.

2. The method of claim 1, wherein the rare-earth phosphate comprises yttrium phosphate, erbium phosphate, holmium phosphate, dysprosium phosphate, thulium phosphate, ytterbium phosphate, lutetium phosphate, terbium phosphate, or combinations thereof.

3. The method of claims 1, wherein the rare-earth phosphate comprises yttrium phosphate.

4. The method of claim 1, wherein the rare-earth phosphate comprises holmium phosphate.

5. The method of claim 1, wherein administering the composition comprises injecting the composition at the target site.

6. The method of claim 1, wherein the occlusion is penetrable by a medical device without reestablishing fluid flow through the lumen.

7. The method of claim 1, wherein the duration of time is less than 90 minutes.

8. The method of claim 1, wherein the duration of time is less than 60 minutes.

9. The method of claim 1, wherein the duration of time is less than 30 minutes.

10. The method of claim 1, wherein the duration of time is from 15 minutes to 30 minutes.

11. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable solution.

12. The method of claim 11, wherein the pharmaceutically acceptable solution is 0.9% saline.

13. The method of claim 1, wherein the composition comprises from about 0.300 mg of rare- earth phosphate particles to about 0.600 mg of rare-earth phosphate particles.

14. The method of claim 1, wherein the target site is a blood vessel.

15. The method of claim 1, wherein the target site is a wound.

16. The method of claim 1, wherein the composition further comprises an imaging agent.

17. The method of claim 1, wherein the bleeding is caused by trauma.

18. The method of claim 1, wherein the bleeding is organ bleeding, gastrointestinal bleeding, vascular bleeding, or bleeding associated with an aneurysm.

19. A composition for use in controlling bleeding, the composition comprising a rare-earth phosphate, wherein the rare-earth phosphate has a xenotime crystal structure, and wherein the rare-earth phosphate forms an occlusion that substantially occludes fluid flow at a target site in the subject for a duration of time of less than 120 minutes20. The composition for use according to claim 19, wherein the rare-earth phosphate comprises yttrium phosphate, erbium phosphate, holmium phosphate, dysprosium phosphate, thulium phosphate, ytterbium phosphate, lutetium phosphate, terbium phosphate, or combinations thereof.

21. The composition for use according to claim 19, wherein the rare-earth phosphate comprises yttrium phosphate, holmium phosphate, or combinations thereof.

22. A method of controlling fluid flow in a subject in need thereof, the method comprising: administering a composition comprising a rare-earth phosphate to a target site within the subject, wherein: the composition forms a penetrable occlusion, andthe penetrable occlusion substantially occludes fluid flow at the target site for a duration of time less than 120 minutes; and inserting a medical device through the penetrable occlusion, wherein inserting the medical device does not reestablish fluid flow at the target site.

23. The method of claim 22, wherein the medical device is a catheter, microcatheter, or microsyringe.

24. The method of claim 22, wherein the body lumen is a blood vessel.

25. The method of claim 22, wherein the composition further comprises an imaging agent.

26. The method of claim 22, wherein administering the composition comprises injecting the composition at the target site.

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