Extracorporeal devices and matrices for removing ammonia from biological fluids, as well as methods and uses thereof.

Abstract

The present invention relates to a device comprising a conjugate and its use in depleting at least one amine, specifically ammonia, from a bodily fluid. The present disclosure further provides systems, apparatus, conjugates, conjugates, and methods. More specifically, the conjugate comprises a particle attached to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group (Formula I), where n is an integer ranging from 5 to 15, m is an integer ranging from 5 to 10, and the scavenger A is characterized by having the ability to capture or bind amines. In some optional embodiments, the amine is at least one of methylamine, dimethylamine, or trimethylamine. In some embodiments, the linker of the conjugate of the disclosed device comprises a linear alkane and m carbonyl groups.

Description

Technical Field

[0001] The present invention relates to the field of plasma exchange. More specifically, the present invention provides specific devices and matrices for depleting ammonia from biological fluids, the resulting ammonia-free biological fluids, as well as methods and uses thereof.

Background Art

[0002] References considered relevant as background to the presently disclosed subject matter are listed below.

[0003] The recognition of the following references in this specification should not be inferred as meaning that they are in any way relevant to the patentability of the presently disclosed subject matter.

[0004] Hepatic encephalopathy is a potentially reversible or progressive neuropsychiatric syndrome characterized by changes in cognitive function, behavior, and personality, as well as transient neurological symptoms and characteristic electroencephalogram patterns associated with acute and chronic liver failure. Hepatic encephalopathy is a frequent complication of cirrhosis commonly observed in association with severe liver failure. Its characteristic symptom is the onset of an acute encephalopathy accompanied by a rapid decline in the level of consciousness, presenting as confusion or stupor. Often, precipitating factors can be identified. Treatment of the episode is targeted at correcting the precipitating factors. When the precipitating state dissipates, the encephalopathy typically also disappears, and the patient recovers to their previous state. However, in patients with low liver reserve capacity, hepatic encephalopathy can be a chronic condition. With low reserve capacity, patients are more likely to develop acute hepatic encephalopathy. One of the main particles again considered in the pathophysiology of HE is ammonia.

[0005] Ammonia, a byproduct of the metabolism of nitrogen-containing compounds, is neurotoxic at high concentrations. The liver removes almost all portal vein ammonia, converting it to glutamine and urea to prevent it from entering the systemic circulation. However, glutamine is metabolized in the mitochondria to produce glutamate and ammonia, and glutamine-derived ammonia can interfere with mitochondrial function, leading to astrocyte dysfunction. Increased blood ammonia in advanced liver disease is a result of liver dysfunction and shunting of blood around the liver. Muscle weakness, commonly seen in these patients, may also contribute, as muscles are an important site for extrahepatic ammonia removal. In addition to direct neurotoxicity, mild astrocyte swelling may contribute to brain dysfunction. The enzyme glutamine synthase (found in the endoplasmic reticulum of astrocytes) plays a role in converting ammonia to glutamine. Because glutamine acts as an osmolyte, water moves within astrocytes, causing mild cerebral edema and a predominance of neurodepression (i.e., slowing of mental processes), which are symptoms of HE associated with chronic liver disease.

[0006] The treatment of encephalopathy using a combination of artificial liver support (ALS) and hemodiafiltration (HDF) has been demonstrated to date (Non-Patent Literature 1).

[0007] Steffen R et al. (Non-Patent Literature 2) have demonstrated that a molecular adsorbent recirculating system (MARS) represents a cell-free extracorporeal liver support method for the selective removal of albumin-binding substances. Furthermore, it enables the removal of excess water and water-soluble substances via an integrated dialysis step.

[0008] Furthermore, Evans et al. (Non-Patent Literature 3) have demonstrated the treatment of anuria using a method involving the introduction of ammonium ion-charged carboxylate ion exchange resin, both orally and via retained enema. They reported successful exchange with potassium ions and a clear decrease in serum potassium concentration.

[0009] The use of ion exchange resins, particularly the British resin ZK.225 having 20% ​​divinylbenzene bonds, has been reported to be effective (Non-Patent Literature 4). When blood was passed from arteries through autoclaved resin columns to veins, a significant amount of ammonia was removed from dog blood, resulting in significantly high levels of ammonia.

[0010] Recent studies have demonstrated that hyperkalemia increases the risk of cardiac arrhythmia episodes and sudden death (Non-Patent Document 5). Therefore, controlling elevated potassium levels is essential to reducing mortality in this population.

[0011] Fujita et al. have demonstrated the effectiveness of potassium adsorption filters in removing ammonia from blood products (Non-Patent Literature 6). This publication shows a potassium adsorption filter (PAF) that can be used at the bedside to remove potassium ions from filled red blood cell (RBC) solution. The disclosed method is reported to be applicable to patients requiring rapid, large-volume blood transfusions and can reduce ammonia concentrations.

[0012] The use of potassium-cycle exchange resins to lower blood ammonia levels in dogs with Eck's fistula has been reported to date (Non-Patent Document 7). The disclosed resins have the advantage of exchanging potassium ions for ammonium and sodium ions.

[0013] U.S. Patent No. 4,183,811(A) (Patent Document 1) discloses a membrane unit and apparatus for removing toxic metabolites and metabolites normally present in urine from blood.

[0014] International Publication No. 2014079681(A2) (Patent Document 2) discloses an extracorporeal system for liver replacement and / or assistance, including a liver dialysis device for performing hemodialysis on patients suffering from liver failure. The system disclosed therein is characterized by comprising: a first standard hollow fiber dialyzer that is perfused with the patient's blood and does not allow an essential amount of albumin to pass through the membrane wall; and a second hollow fiber dialyzer that receives blood from the first standard hemodialysis unit and allows an essential but specified amount of albumin to pass through the membrane wall. The filtrate space is closed off from the luminal space of the hollow fibers and is occupied by an adsorbent material that may contain one or more different adsorbents.

[0015] International Publication No. 2016205221(A1) (Patent Document 3) discloses an extracorporeal filtration and detoxification system and method for separating ultrafiltrate from the cellular components of blood. The method includes treating the ultrafiltrate independently of the cellular components in a recirculation circuit, remixing the treated ultrafiltrate with the cellular components, and returning the whole blood to the patient.

[0016] International Publication No. 2004014315(A2) (Patent Document 4) demonstrates a method for removing fractions containing substances within a specific molecular weight range from a patient's blood and / or specific plasma.

[0017] U.S. Patent No. 3,963,613(A) (Patent Document 5) discloses a blood purification means in which the blood of a patient being treated is guided around an external circuit connected to the patient's blood flow and brought into direct or indirect contact with a fumaric acid solution. The blood is further brought into contact with an enzyme preparation, preferably an aspartase preparation, which catalyzes the reaction of L-aspartic acid formation from fumaric acid and ammonia. The purification means may further include one or more preliminary steps that can decompose unwanted substances in the patient's blood into non-toxic substances and ammonia, which are then converted to aspartic acid, and may also include a low-molecular-weight sieving means to prevent the generated aspartic acid from re-entering the patient's blood flow.

[0018] Patent Publication No. 2008093244(A) (Patent Document 6) discloses a method for efficiently removing ammonia contained in liquids such as blood or plasma by using silica gel. However, it should be noted that the filter disclosed in this publication is not specific to ammonia and may also deplete other small particles such as lipopolysaccharides. Furthermore, most currently available raisins are based on ion exchange materials that can remove ammonia from plasma, but are not specific to ammonia only. It should be understood that since ammonia is cationic at physiological pH, it can be bound by any cation exchanger that is not specific to ammonia only. Therefore, there is a need for a resin specifically designed to remove only ammonia from plasma, such as the one disclosed in the present invention.

[0019] Chinese Patent No. 100486651(C) (Patent Document 7) demonstrates a multi-organ function support system formed by a main unit, an external blood circuit, a plasma separation-adsorption circuit, an albumin circuit, a dialysate circuit, a supply circuit, and an operating system. This disclosure further discloses a system for removing inflammatory media, toxins, and small molecule substances (e.g., blood ammonia) from the body fluids of patients suffering from multiple organ function impairment complex symptom (MODS). This disclosure also discloses a pulmonary membrane oxygen generator that replaces the air exchange function of the lungs, and its use in reverse exhalation.

[0020] Chinese Patent No. 109692372(A) (Patent Document 8) discloses a five-layer hemoperfusion device and hemoperfusion method. More specifically, an anticoagulant layer of gel microballs, a β2-microglobulin adsorption layer, a urea decomposition layer, an ammonia adsorption layer, and an activated carbon adsorption layer are continuously arranged along the direction of blood flow within the perfusion device ontology. The hemoperfusion method provided therein relates to purifying up to 7000 μg of ammonia from blood. However, it is necessary to remove extremely large amounts of ammonia.

[0021] Therefore, in this field of technology, there is a need for effective means and methods for depleting ammonia from bodily fluids. [Prior art documents] [Non-patent literature]

[0022] [Non-Patent Document 1] Treatment of hepatic encephalopathy by online hemodiafiltration: a case series study, Shinju Arata, Katsuaki Tanaka, Kazuhisa Takayama, Yoshihiro Moriwaki, Noriyuki Suzuki, Mitsugi Sugiyama & Kazuo Aoyagi, May 21, 2010 [Non-Patent Document 2] Extracorporeal Detoxification Using the Molecular Adsorbent Recirculating System for Critically Ill Patients with Liver Failure Steffen R.Mitzner,Jan Stange,Sebastian Klammt,Piotr Peszynski,Reinhardt Schmidt and Gabriele Noldge-Schomburg Jasn February 2001,12(suppl 1)S75-S82 [Non-Patent Document 3] Ion-exchange resins in the treatment of anuria bmevans.et al Lancet 1953 [Non-Patent Document 4] Extracorporeal methods of reducing high blood ammonia levels H.D.Ritchie,D.M.Davies,J.M.Godfrey,P.Fan,R.G.S.Johns,and J.Perrin,Gut,1962

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Patent Document

[0023]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

[0024] A first aspect of the present invention is: - A housing comprising at least one fluid inlet port and at least one fluid outlet port, - The housing comprises at least one chamber, the at least one chamber, and the device defines a control volume that is in fluid communication with at least one fluid inlet port and at least one fluid outlet port. In some embodiments, the control volume accommodates at least one of a conjugate, a plurality of conjugates, or at least one composition comprising a conjugate or a plurality of conjugates. More specifically, the conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to capture or bind amines. In some optional embodiments, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0025] In some embodiments, the linker of the conjugate of the disclosed device comprises a linear alkane and m carbonyl groups.

[0026] In some further embodiments, the linear alkane is either saturated or unsaturated.

[0027] Furthermore, in some embodiments, the linear alkane of the conjugate in the disclosed device is unsaturated.

[0028] In certain embodiments, the linear chain contains 1 to 3 double bonds.

[0029] Furthermore, in some embodiments of the disclosed device, the amine is ammonia.

[0030] In some further embodiments, the linker of the conjugate of the disclosed device is such that the m-th carbonyl is linearly bonded. [ka] via, or another short alkane chain [ka] The scavenger is covalently bonded to the scavenger so as to be bonded through the scavenger, where X is an integer in the range of 1 to 3.

[0031] In some embodiments, the conjugate scavenger of the disclosed device is a strong acid capable of capturing ammonia.

[0032] Furthermore, in some embodiments, the strong acid is sulfuric acid or any derivative thereof.

[0033] In some further embodiments, the length (n) of the linear alkane is 15.

[0034] In a particular embodiment, the conjugate of the disclosed device comprises a particle bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and an acid A covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula II. [ka] In the equation, x ranges from 0 to 3.

[0035] Furthermore, in some embodiments, the conjugate of the disclosed device comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. [ka] In the equation, x ranges from 0 to 3.

[0036] In some embodiments, the particles and the linker are covalently bonded, and the bond is a covalent bond via an amino group shown in formula IV. [ka]

[0037] In a particular embodiment, the conjugate of the disclosed device has structural formula V. More specifically, the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0038] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads, and therefore the resin beads are an agarose resin that may contain about 2% to 10% agarose in some embodiments. Furthermore, in some embodiments, the resin beads may contain 3% to 9% agarose, and furthermore, in some embodiments, the resin beads may contain 4% to 8% agarose. According to further specific, any non-limiting embodiments, the resin beads optionally contain at least 4% agarose.

[0039] In some further embodiments, the resin bead size is in the range of 40 to 170 μm.

[0040] In some further embodiments, the device comprises a first barrier member and a second barrier member spaced longitudinally apart from each other across the contrasting volume, the first barrier member and the second barrier member each configured to allow unidirectional fluid flow through each barrier member and to block unidirectional fluid flow through each barrier member.

[0041] In some embodiments, the first barrier member and the second barrier member are installed within the device to allow fluid flow through the device from at least one fluid inlet port to at least one fluid outlet port, and at the same time to block fluid flow from the fluid outlet port to the fluid inlet port.

[0042] In further embodiments of some of the disclosed devices, each of the first barrier member and the second barrier member comprises a film made from a preferred material.

[0043] Furthermore, the housing comprises an outer casing, an inlet end cap, and an outlet end cap, the outer casing having an outer wall extending longitudinally between the inlet end and the outlet end of the outer casing. The inlet end cap is configured to be sealed to the inlet end, and the outlet end cap is configured to be sealed to the outlet end.

[0044] In further embodiments of the devices according to this disclosure, the inlet end cap, the outlet end cap, and the outer casing are each made from a suitable medically compatible material.

[0045] In a particular embodiment, the inlet end cap is configured as a self-locking cap to the outer casing and is configured to allow the inlet end cap to be sealed and locked in a predetermined position to the outer casing.

[0046] Furthermore, in some embodiments, the disclosed device includes a first self-locking device configured to enable the inlet end cap to self-lock to the outer casing.

[0047] In some embodiments, the first self-locking device comprises a plurality of first wedge elements and a first flange device. Furthermore, the first wedge elements are provided within the inlet end cap, and the first flange device is provided within the outer casing at a longitudinal distance of a first interval from the inlet end, and the first wedge elements are configured to cooperate with the first flange stop device to provide self-locking of the inlet end cap to the housing.

[0048] In some further embodiments of the disclosed devices, each of the first wedge elements protrudes longitudinally away from the free end of the first end cap.

[0049] In some embodiments, the first gap is sufficient to ensure that each free end of the inlet end cap contacts the first flange device when the inlet end cap is fully engaged with the outer casing.

[0050] In some embodiments of the disclosed device, the first flange stopper includes a plurality of first stopper elements corresponding to a plurality of first wedge elements. Furthermore, each of the first stopper elements operates to prevent the inlet end cap from disengaging from the outer casing when the respective first wedge element is in contact with the outer casing.

[0051] In some embodiments of the disclosed devices, the first flange stopper comprises a first flange including a plurality of first notches corresponding to first wedge elements. Furthermore, each of the first notches has a circumferential length and axial depth sufficient to accommodate therein each of the first wedge elements in the locking configuration.

[0052] In some embodiments, the outlet end cap is configured as a self-locking cap to the outer casing and is configured to allow the outlet end cap to be sealed and locked in place to the outer casing.

[0053] In some embodiments, the device of the present disclosure includes a second self-locking device configured to enable self-locking of the outlet end cap to the outer casing.

[0054] In a more specific embodiment of the disclosed device, the second self-locking device comprises a plurality of second wedge elements and a second flange device. The second wedge elements are provided within the outlet end cap, and the second flange device is provided within the outer casing at a longitudinal distance of a second interval from the outlet end. Furthermore, the second wedge elements are configured to cooperate with the second flange stop device to provide automatic locking of the outlet end cap to the housing.

[0055] In some embodiments, each of the second wedge elements protrudes longitudinally away from the free end of the second end cap.

[0056] In some further embodiments of the disclosed device, the second spacing is sufficient to ensure that each free end of the outlet end cap contacts the second flange device when the outlet end cap is fully engaged with the outer casing.

[0057] In some further embodiments, the second flange stop device comprises a plurality of second stop elements corresponding to a plurality of second wedge elements. Furthermore, each of the second stop elements operates to prevent the outlet end cap from disengaging from the outer casing when the respective second wedge element is in contact with the outer casing.

[0058] In some embodiments, the second flange stopper comprises a second flange including a plurality of second notches corresponding to second wedge elements. Furthermore, each of the second notches has a circumferential length and axial depth sufficient to accommodate each second wedge element therein in the locking configuration.

[0059] In some embodiments of the disclosed device, the control volume is approximately 250 ml to approximately 350 ml. In some further embodiments, the control volumes are approximately 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, and 350 ml. Furthermore, in some embodiments, the control volume is approximately 257 ml to approximately 326 ml.

[0060] In some embodiments, the devices of the present disclosure are configured for use in depleting at least one amine from at least one liquid substance.

[0061] In some specific embodiments, the amine depleted by the disclosed device is ammonia.

[0062] In some further embodiments, the device of the present invention is configured to deplete at least one amine from a liquid substance that may be a mammalian body fluid. Thus, in some embodiments, the device is intended for use in depleting ammonia from a mammalian body fluid.

[0063] In some specific embodiments, the conjugate of the disclosed device has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the mth carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0064] Further aspects of this disclosure are: -At least one device as defined in this disclosure, - Apheresis machines and, - A blood mixture reservoir, - A system comprising a conduit system and

[0065] In some embodiments, the conduit system comprises a first conduit configured to provide selective fluid communication between an apheresis machine and the body of an object requiring it, thereby allowing blood to flow from the body of the object requiring it to the apheresis machine.

[0066] In some embodiments, the conduit system includes a second conduit configured to provide fluid communication from the plasma outlet of the apheresis machine and at least one device, thereby allowing plasma separated from the blood by the apheresis machine to flow into at least one device.

[0067] Furthermore, in some embodiments, the conduit system includes a third conduit configured to provide fluid communication from at least one device to a blood mixture reservoir, thereby allowing treated plasma treated by at least one device to flow into the blood mixture reservoir.

[0068] In a particular embodiment, the conduit system includes a fourth conduit configured to provide fluid communication from the blood product outlet of the apheresis machine to a blood mixture reservoir, thereby allowing other blood products separated from the blood by the apheresis machine to flow into the blood mixture reservoir.

[0069] In some further embodiments, the conduit system comprises a fifth conduit configured to provide selective fluid communication between a blood mixture reservoir and the body of an object requiring it, thereby allowing treated blood to flow from the blood mixture reservoir to the body of an object requiring it.

[0070] It should be noted that in some embodiments of the disclosed system, the subjects requiring it are those suffering from at least one disorder associated with elevated blood ammonia levels. Specifically, these are any of the disorders considered in relation to other embodiments of the present invention.

[0071] In some embodiments, the disclosed system comprises a plurality of devices disclosed herein, interconnected in series with respect to one another.

[0072] In some further embodiments, the disclosed system comprises a plurality of such devices interconnected in parallel with respect to each other via inlet manifolds coupled to each fluid inlet port and outlet manifolds coupled to each fluid outlet port.

[0073] In some further embodiments, the disclosed system comprises a first plurality of groups of devices, the groups interconnected in parallel with respect to one another via inlet manifolds coupled to each fluid inlet port and via outlet manifolds coupled to each fluid outlet port, and each group comprises a second plurality of devices interconnected in series with respect to one another within its own group.

[0074] A further aspect of this disclosure relates to batteries for use in depleting ammonia from mammalian bodily fluids, including a plurality of devices as defined by this disclosure.

[0075] Further aspects provided by this disclosure relate to batteries for use in depleting ammonia from mammalian bodily fluids, including a plurality of devices as defined by this disclosure.

[0076] Further aspects of the present disclosure relate to an external device comprising at least one conjugate, or at least one device containing a conjugate, or at least one device or battery connected to a device. More specifically, the conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. Furthermore, the device is - A housing comprising at least one fluid inlet port and at least one fluid outlet port, - The housing includes at least one chamber, the at least one chamber defining a control volume that is in fluid communication with at least one fluid inlet port and at least one fluid outlet port. The control volume contains at least one of the following: a conjugate, multiple conjugates, or at least one composition comprising a conjugate or multiple conjugates.

[0077] Further embodiments relate to an external device comprising at least one conjugate, or at least one device comprising a conjugate. In some embodiments, the external device may be connected to such at least one device or a battery of the device. In more specific embodiments, the conjugate of the external device of the present disclosure may comprise a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10. More specifically, the scavenger A is characterized by having the ability to scavenge or bind an amine, and optionally the amine is at least one of methylamine, dimethylamine, or trimethylamine. In some further embodiments, the device contained within or connected to an external device is - A housing may have at least one fluid inlet port and at least one fluid outlet port. - The housing includes at least one chamber, which defines a reference volume that is in fluid communication with at least one fluid inlet port and at least one fluid outlet port. The reference volume accommodates at least one conjugate, a plurality of conjugates, or at least one composition comprising a conjugate or a plurality of conjugates.

[0078] In some embodiments of the external devices of this disclosure, the device is as defined herein, and the battery is as defined herein. In some embodiments, the conjugate, multiple conjugates or compositions, device and battery used in the external device are as defined herein.

[0079] In some embodiments, the external devices of this disclosure are applicable to use in depleting ammonia from mammalian body fluids.

[0080] Further aspects of this disclosure relate to a conjugate having structural formula I. More specifically, the conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines, and optionally the amine is at least one of methylamine, dimethylamine, or trimethylamine. Furthermore, in some embodiments, having the ability to scavenge means binding and / or scavenging at least one amine.

[0081] In some embodiments, the linker of the disclosed conjugate comprises a linear alkane and m carbonyl groups.

[0082] Furthermore, in some embodiments, the linear alkane of the disclosed conjugate is either saturated or unsaturated.

[0083] In some embodiments, the linear alkane is unsaturated.

[0084] In some further embodiments, the linear chain contains 1 to 3 double bonds.

[0085] Furthermore, in some embodiments, the conjugate scavenger A of the present disclosure has the ability to scavenge and / or bind at least one amine, specifically, the amine being ammonia.

[0086] In further embodiments of some of the disclosed conjugates, the linker is such that the m-th carbonyl is linearly bonded. [ka] via, or another short alkane chain [ka] The scavenger is covalently bonded to the scavenger so as to be bonded through the scavenger, where X is an integer in the range of 1 to 3.

[0087] Furthermore, in some embodiments, the conjugate scavenger disclosed is a strong acid capable of capturing ammonia.

[0088] In some further embodiments, the strong acid is sulfuric acid or any derivative thereof.

[0089] In some embodiments, the length (n) of the linear alkane is 15.

[0090] Furthermore, in some embodiments, the conjugate of the present disclosure comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and acid A covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula II. [ka] In the equation, x ranges from 0 to 3.

[0091] In some further embodiments, the conjugate comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. [ka] In the equation, x ranges from 0 to 3.

[0092] In some embodiments of the conjugates disclosed herein, the particles and the linker are covalently bonded, and the bond is a covalent bond via an amino group as shown in Formula IV. [ka]

[0093] Furthermore, in some embodiments, the conjugate disclosed herein has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0094] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads, and therefore the resin beads are an agarose resin that may contain about 2% to 10% agarose in some embodiments. Furthermore, in some embodiments, the resin beads may contain 3% to 9% agarose, and further, in some embodiments, the resin beads may contain 4% to 8% agarose. In some further embodiments, the particles of the disclosed conjugate are resin beads. Furthermore, the resin beads optionally contain at least 4% agarose.

[0095] In some embodiments of the disclosed conjugate, the resin bead size is in the range of 40 to 170 μm.

[0096] Further aspects of the present disclosure relate to a plurality of conjugates or any composition comprising such plurality of conjugates. Each conjugate comprises a particle, at least one linker, and at least one scavenger A, or any derivative or analog thereof, wherein the conjugate comprises a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0097] In some embodiments, the conjugates of a plurality of conjugates are any of the conjugates disclosed herein.

[0098] In some embodiments, the multiple conjugates disclosed herein are intended for use in depleting at least one amine from at least one liquid substance.

[0099] In some embodiments of the multiple conjugates disclosed, the amine is ammonia.

[0100] In some embodiments, the liquid substance is a mammalian bodily fluid.

[0101] Furthermore, in some other embodiments, multiple conjugates are intended for use in depleting ammonia from the bodily fluids of mammals.

[0102] Further aspects of the present disclosure relate to a method for depleting at least one amine from a liquid substance. More specifically, the method comprises the following steps: In a first step (i), the liquid substance is subjected to an affinity depletion procedure specific to at least one amine. The next step (ii) comprises recovering the liquid depleted of at least one amine obtained in step (i). In some embodiments, the affinity depletion procedure comprises contacting the liquid substance with an effective amount of at least one conjugate, a plurality of conjugates, or a composition comprising a conjugate or a plurality of conjugates, or applying the liquid substance onto a device, battery, or external device comprising the conjugates of the present disclosure. In a more specific embodiment, each conjugate comprises a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0103] In some embodiments, the liquid substance used in the methods of the present disclosure is a mammalian bodily fluid or any product thereof.

[0104] In some further embodiments, the method of the present invention is used to deplete at least one amine from any liquid substance. In some embodiments, the amine is ammonia. Thus, in some embodiments, the method of the present disclosure is for use in depleting ammonia from the body fluids of mammals.

[0105] It should be noted that in some embodiments, any conjugate, multiple conjugates or compositions, devices and / or batteries and / or apparatus used by the methods discussed herein are defined by the present invention.

[0106] A further aspect of the present invention relates to a method for depleting at least one amine from a bodily fluid of a subject requiring such depletion. More specifically, the method may involve contacting the bodily fluid with an effective amount of conjugates, a plurality of conjugates or compositions thereof, or in a device or battery containing conjugates, or alternatively, with an extracorporeal device containing or connected to a conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step includes recovering amine-free body fluid and, optionally, reintroducing this body fluid to the desired target.

[0107] In some further specific, non-limiting embodiments, the method may include the use of an in vitro procedure. More specifically, such a method may include the following steps: First, in step (i), the target bodily fluid is transferred to an extracorporeal device. The next step (ii) involves subjecting the body fluid to an affinity depletion procedure specific to at least one amine, which is performed before, during, or after the blood is transferred in or out of the device, thereby obtaining the extracorporeal body fluid of the subject from which at least one amine has been depleted. The next step (iii) includes reintroducing or returning the body fluid obtained in step (ii) to the target. As described above, the affinity depletion procedure includes contacting the target body fluid with an effective amount of conjugate, multiple conjugates, or a composition thereof contained within the extracorporeal device or within a device or battery connected to the extracorporeal device. Each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0108] In some embodiments, the conjugate, multiple conjugates or compositions, devices, batteries and apparatus used by the method of the present invention are any of those disclosed herein.

[0109] In some embodiments, the conjugate used by the method of the present disclosure has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0110] Further aspects of this disclosure relate to methods for treating, preventing, remedying, improving, or inhibiting disorders or pathological conditions associated with elevated blood ammonia levels in subjects requiring such treatment, by depleting ammonia from the body fluids of subjects requiring such treatment.

[0111] More specifically, the therapeutic methods disclosed herein may involve contacting a body fluid to be treated with an effective amount of a conjugate, a plurality of conjugates or a composition thereof, or in a device or battery containing a conjugate, or alternatively, with an extracorporeal device containing or connected to a conjugate or device disclosed herein. It should be noted that each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step includes recovering amine-free body fluid and, optionally, reintroducing this body fluid into the treated subject.

[0112] In some further specific and non-limiting embodiments, the method may include the use of an in vitro procedure. More specifically, such a method may include the following steps: First, in step (i), the target bodily fluid is transferred to an extracorporeal device. The next step (ii) involves subjecting the body fluid to an affinity depletion procedure specific to at least one amine, which is performed before, during, or after the blood is transferred in or out of the apparatus, thereby obtaining the extracorporeal body fluid of the treated subject from which at least one amine has been depleted. The next step (iii) includes reintroducing or returning the body fluid obtained in step (ii) to the target. As described above, the affinity depletion procedure includes contacting the target body fluid with an effective amount of conjugate, multiple conjugates, or a composition thereof contained within the extracorporeal device or within a device or battery connected to the extracorporeal device. Each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0113] In some embodiments, the conjugate, multiple conjugates or compositions, devices, batteries and apparatus used by the therapeutic method of the present invention are any of those disclosed herein.

[0114] In some embodiments, the conjugate used by the therapeutic method of the present disclosure has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0115] In some embodiments, the methods of the present disclosure may be any disorder associated with elevated blood ammonia levels, a chronic hepatic or pulmonary condition and / or cognitive impairment, and / or hyperammonemia and related conditions.

[0116] In some specific embodiments, the liver condition is hepatic encephalopathy and any related conditions.

[0117] These and other aspects of the present invention will become clear from the following disclosure. [Brief explanation of the drawing]

[0118] Embodiments are described herein, only as non-limiting examples, with reference to the accompanying drawings, in order to better understand the subject matter disclosed herein and to illustrate how it can actually be carried out.

[0119] [Figure 1] These are isometric and partial break diagrams of a device according to one embodiment of the subject matter of this disclosure. [Figure 2] This is an isometric exploded view of the embodiment shown in Figure 1. [Figure 3]Figure 3(a) is a side view of the outer casing of the embodiment shown in Figure 1. Figure 3(b) is a front view of the embodiment shown in Figure 3(a). Figure 3(c) is a side cross-sectional view along BB of the embodiment shown in Figure 3(b). [Figure 4-1] Figure 4(a) is a side view of the inlet cap of the embodiment shown in Figure 1. Figure 4(b) is a cross-sectional side view of the embodiment shown in Figure 4(a) along AA. [Figure 4-2] Figure 4(c) is a rear isometric view of the embodiment shown in Figure 4(a). Figure 4(d) is a front isometric view of the embodiment shown in Figure 4(a). [Figure 5-1] Figure 5(a) is a side view of the outlet cap according to the embodiment in Figure 1. Figure 5(b) is a cross-sectional side view of the embodiment in Figure 5(a) along A'-A'. [Figure 5-2] Figure 5(c) is a rear isometric view of the embodiment shown in Figure 5(a). Figure 5(d) is a front isometric view of the embodiment shown in Figure 5(a). [Figure 6] This is a partially isometric exploded view of the first self-locking device according to the embodiment shown in Figure 1. [Figure 7] This is a partially isometric exploded view of the second self-locking device according to the embodiment shown in Figure 1. [Figure 8] This is a cross-sectional side view of the first barrier member assembly in the embodiment shown in Figure 1. [Figure 9] This is a cross-sectional side view of the second barrier member assembly of the embodiment shown in Figure 1. [Figure 10] This is a schematic diagram illustrating a system according to one embodiment of the subject matter of this disclosure. [Figure 11] This is a schematic diagram illustrating an alternative modification of the embodiment shown in Figure 10. [Figure 12] This is a schematic diagram illustrating a different alternative modification of the embodiment shown in Figure 10. [Figure 13] This is a schematic diagram illustrating a different alternative modification of the embodiment shown in Figure 10. [Figure 14] This is a schematic diagram illustrating a different alternative modification of the embodiment shown in Figure 10. [Figure 15](Conjugate with sulfonic acid) This figure shows a schematic diagram of the chemical reaction for preparing the conjugate with sulfonic acid. [Figure 16] (Ammonia Standard Curve) This graph represents the standard curve used for calculating ammonia concentration. [Figure 17] (Establishment of a high-ammonia model in pigs) Figure 17A shows an example of pigs that were anesthetized and administered xylazine and ketamine via central venous infusion. Figure 17B shows a histogram of ammonia concentrations monitored every 30 minutes before and after the procedure. [Figure 18] (Ammonia Depletion Procedure) This figure illustrates the procedure for depleting ammonia from human plasma units. A plasma bag is connected to the ammonia depletion device of this disclosure. A flow regulator regulates the flow of plasma to the device, and a clamp is used to stop the flow in case of leakage. The filtered blood product is then collected in the bag. [Figure 19] (Ammonia Depletion Procedure in Human Plasma) A human plasma bag (ammonia-enriched) was connected to the device of this disclosure (referred to herein as the AAPC-300 filter) by a Luer locking connection. The plasma flowed through the device at a controlled rate of 150 mL / min (controlled by the flow regulator shown in Figure 18). The plasma was collected in a 200 mL tube. To evaluate the rate of ammonia depletion, the filtered plasma was subjected to an Elisa reader. Statistics were calculated using Student's t-test (two-sided, equal variances). Data are expressed as mean ± SD. [Modes for carrying out the invention]

[0120] In its broadest aspect, this disclosure provides a conjugate, a plurality of conjugates, and a composition comprising a plurality of conjugates, each conjugate having a general formula (I'), XYZ (I') During the ceremony, X is a solid support portion, such as particles. Y is a chemically reactive part that binds parts X and Z. Z is a portion comprising at least one of a scavenger, its derivative, or its analogue. Each "-" indicates an interaction / association, for example, a chemical bond that optionally contains one or more intervening atoms that function as a spacer or selectively directed portion. Therefore, in the first aspect, the present invention is - A housing comprising at least one fluid inlet port and at least one fluid outlet port, - The housing includes at least one chamber, which defines a control volume that is in fluid communication with at least one fluid inlet port and at least one fluid outlet port. The control volume provides a device that accommodates at least one of a conjugate, a plurality of conjugates, or at least one composition comprising a conjugate or a plurality of conjugates. In some specific embodiments, the conjugate of the device disclosed herein has structural formula I, and the conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10. In some embodiments, the scavenger A is characterized by having the ability to scavenge or bind amines. As described above, in some embodiments, the linker contains 5 to 15 carbon atoms. In some embodiments, the length of one carbon atom is about 1.5 angstroms, so therefore, in some embodiments, the length of the linker may be in the range of 7.5 angstroms or less to 22.5 angstroms or more. In some further embodiments, the linker further contains 5 to 10 carbonyls. Since each carbonyl can be about 1.3 angstroms in length, this length may be in the range of about 6.5 angstroms or less to about 13 angstroms or more.

[0121] In other words, this disclosure is in three parts, namely -particles and, -Linker and, - Provides a device including a conjugate containing a scavenger.

[0122] The three parts are bonded together so that the linker connects the particles and the trapping agent.

[0123] The linker of the present invention generally comprises two groups, the first of which comprises a linear alkane containing n carbon atoms and a group of m covalently bonded carbonyl groups.

[0124] In some embodiments, the linear alkane of the linker of the conjugate of the device of the present disclosure is either saturated or unsaturated.

[0125] In some embodiments, the linear alkane group may be saturated, while in other embodiments, the group may be unsaturated.

[0126] In embodiments where the linear alkane group is unsaturated, the chain may contain 1 to 3 double bonds.

[0127] The scavenger portion, as indicated herein as A, may include any agent having the ability to “scavenge” or bind amines.

[0128] In the context of this disclosure, the term amine refers to any compound or functional group containing at least one basic nitrogen atom having at least one lone pair of electrons. Examples of amines according to this disclosure include any primary, secondary, and tertiary amines having a molecular weight (MW) of at least 17 to a maximum of 70 daltons.

[0129] In some embodiments, the amine is an alkylamine, dialkylamine, or trialkylamine, and the MW of such amine is 17 to 70 daltons.

[0130] In some other embodiments, the amine is selected from methylamine, dimethylamine, or trimethylamine.

[0131] In certain embodiments, the amine is ammonia.

[0132] The linker of the present invention has a linear bond at the m-th carbonyl group. [ka] via, or another short alkane chain [ka] The scavenger is covalently bonded to the scavenger via a bond, where X is an integer between 1 and 3.

[0133] In some embodiments, the scavenger can be any ion exchange material. More specifically, ammonia can bind to a cation exchanger because it is cationic at physiological pH. Other alternatives included in the present invention are NHS and epoxy.

[0134] In some embodiments, the scavenger is an acid.

[0135] In some embodiments, the acid is a strong acid capable of capturing the amine.

[0136] In some embodiments, the amine is as defined above.

[0137] In some other embodiments, the amine is ammonia.

[0138] In the context of the disclosures provided herein, the term “strong acid” is any acid having a pKa value less than 1.

[0139] Sometimes the pKa is lower than 0, sometimes lower than (-1), sometimes lower than (-2), sometimes lower than (-3), sometimes lower than (-4), sometimes lower than (-5), sometimes lower than (-6), sometimes lower than (-7), sometimes lower than (-8), and sometimes lower than (-9).

[0140] In some specific embodiments, the acid is selected from the group consisting of chloric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, hydroiodic acid, their analogs and derivatives.

[0141] In certain embodiments, the acid is sulfuric acid or a derivative thereof.

[0142] A derivative of a sulfonic acid can be any molecule having the following general formula: [ka] In the formula, R is an organoalkyl or aryl group.

[0143] In the embodiment, the sulfonic acid derivative is selected from taurine, PFOS, p-toluenesulfonic acid, and coenzyme M.

[0144] In some embodiments, R is -H.

[0145] In most common terms, the length of a linear alkane determines the specificity of the conjugate. Linkers that are too long trap nonspecific / undesirable molecules such as proteins and amino acids (because they contain amino groups). Short linkers reduce the conjugate's ability to trap ammonia and ammonium cations.

[0146] Therefore, in some embodiments, the length (n) of the linear alkane is 5 to 20 carbon atoms, specifically 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 1 to 20, 12 to 20, 13 to 20, 14 to 20, and 15 to 20. In some further embodiments, the length (n) of the linear alkane is sometimes 10 to 15, sometimes 12 to 15, sometimes 13 to 15, and sometimes 14 to 15. In some specific embodiments, the length (n) of the linear alkane is 5 or less, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or greater. In certain non-limiting embodiments, n is 15.

[0147] While we do not wish to be bound by theory or mechanism, the carbonyl moiety provides a suitable bulk to prevent the binding of amino acids and peptides to the acidic moiety of the conjugate. Surprisingly, the inventors of this disclosure have found that 5 to 10 carbonyl groups bound together provide a suitable bulk to prevent larger molecules from being trapped by the acidic moiety of the conjugate.

[0148] In another embodiment of the present invention, a device is provided, and the conjugate of the disclosed device comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and acid A covalently bonded to the m-th carbonyl group, the conjugate having structural formula II, [ka] In the equation, x ranges from 0 to 3.

[0149] When x is 0, the m-th carbonyl group is directly bonded to the acid.

[0150] In some further embodiments, the present invention provides a device comprising a conjugate comprising a particle bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. [ka] In the equation, x ranges from 0 to 3.

[0151] In some embodiments, x is between 0 and 2, and sometimes between 0 and 1. Sometimes x is 1, and sometimes x is 0.

[0152] When x is 0, the m-th carbonyl group is directly bonded to the acid.

[0153] In some embodiments, the conjugate of the device of this disclosure is configured to act as an amine trap that exhibits an amine neutralization reaction. In more specific embodiments, the amine is ammonium.

[0154] Furthermore, in some embodiments, the linker portion of the conjugate of the present disclosure is connected to the particles via any suitable functional group that enables the particles to be connected to a linear alkane.

[0155] Without being bound by theory or reaction mechanism, the conjugate of the present invention acts as an amine trap exhibiting a neutralization reaction of one amine as defined above for each acid scavenger in the following manner: [ka] In the formula, -H represents the free hydrogen atom of the acid, and (:) represents the free electron of the amine.

[0156] In embodiments where the acid is a sulfonic acid and the amine is ammonia, the proton (H + )teeth, [ka] The two free electrons of ammonia are donated to form an ionic bond between the conjugate acid and the conjugate base.

[0157] The linker portion of the disclosure herein may be attached to the particles via any group known in the art that enables the particles to be attached to a linear alkane.

[0158] In one possible embodiment, the particles and the linker are covalently bonded.

[0159] In another optional embodiment, the bond is a covalent bond via an amino group, as shown in formula IV. [ka]

[0160] In some other embodiments, the present invention intends a device comprising at least one conjugate having structural formula V, where n is 15, m is an integer between 5 and 10, x is 0, and A is a sulfonic acid. [ka]

[0161] The present invention provides at least one device comprising at least one conjugate. As used herein, a conjugate refers to a compound constructed from certain elements (components), including at least one particle, at least one linker, and at least one scavenger, specifically, in some embodiments, an ammonia scavenger which may be a sulfonic acid or any derivative or analog thereof, all of which associate with it. While this application refers to "at least one particle," it should be noted that any solid support applicable to any of the claimed conjugates is encompassed herein.

[0162] Any one of the conjugates of the devices of the present disclosure of the present invention, or any composition thereof, may also be referred to as a composition of substance. In the most common terminology, “composition of substance” as well as “conjugate” are both used interchangeably and refer to an association of at least one particle, at least one linker, and at least one scavenger, its derivatives or analogs, which may result in properties attributable to the entire composition of substance (or conjugate), but not to any one of the components of the conjugate in their separate states, as detailed below.

[0163] In some embodiments, any one of the conjugates of the device of the Disclosure comprises the association of at least one particle with at least one chemically reactive portion which is a linker, and the association of at least one linker with at least one scavenger, specifically a sulfonic acid and its derivatives or analogs, so that the linker is located between the particle and the scavenger, its derivatives or analogs, and thus associates with the particle at one end (with one arm) and with the scavenger, its derivatives or analogs at the other end (with a second different arm).

[0164] In some embodiments, the scavenger, specifically sulfonic acid and its derivatives, specifically and selectively binds to a particular target, in this case at least one amine, such as ammonia, enabling the effective capture, immobilization, distribution, and removal of ammonia from liquid substances, specifically body fluids.

[0165] As used herein, the term “association” or any linguistic variation thereof means a chemical or physical force that holds two entities together (e.g., a particle and a linker). Such a force may be any type of chemical or physical bonding interaction known to those skilled in the art.

[0166] Non-limiting examples of such association interactions include covalent bonds, ionic bonds, coordination bonds, complex formation, hydrogen bonds, van der Waals bonds, and hydrophobic-hydrophilic interactions. Therefore, the association / conjugation of a linker with at least one particle, and the association / conjugation of a linker with a scavenger, may be via any chemical bond, including covalent bonds, electrostatic interactions, acid-base interactions, van der Waals interactions, etc. As can be understood, the association of a particle with a linker, and the association of a linker with a scavenger, its derivatives, or analogues, may be the same or different, as will be further detailed below.

[0167] The particles of the present invention may include any polymer particles that can be bonded to the linker of the present invention.

[0168] In some embodiments, the particles of the disclosed device are resin beads.

[0169] As used herein, the term "particle" refers to a part of a substance having a surface to which it can be bonded to chemical or biological compounds, small molecules or large molecules, which can be bonded either via covalent or non-covalent bonds. Particles may include porous materials. Particles may be, for example, "spherical" (generally referring to a substantially (almost) round ball shape) or "non-spherical" (having an "elongated" shape with defined long and short axes). Non-limiting examples of particles include beads such as polysaccharide beads, glass beads, cotton beads, plastic beads, nylon beads, latex beads, magnetic beads, paramagnetic beads, superparamagnetic beads, starch beads, etc., as well as at least one of silicon beads, PTFE beads, polystyrene beads, gallium arsenide beads, gold beads, or silver beads. In some embodiments, particles are agarose beads, optionally, beads containing different degrees of crosslinking at different percentages of the material (agarose).

[0170] Therefore, agarose beads encompass beads containing agarose of various degrees of crosslinking, such as beads referred to as Sepharose beads. In some embodiments, the beads include agarose beads. In some embodiments, the beads include Sepharose beads. In some embodiments, the conjugates include a combination of particles containing agarose beads and Sepharose beads. It should be noted that according to this disclosure, particles that are either agarose beads or Sepharose beads are considered to be two different conjugates having different particles.

[0171] Sepharose is the trade name for cross-linked agarose beads, a polysaccharide polymer material extracted from seaweed. Its trademark name is derived from Separation-Pharmacia-Agarose. Sepharose is a registered trademark of GE Healthcare (formerly Pharmacia, Pharmacia LKB Biotechnology, Pharmacia Biotech, Amersham Pharmacia Biotech, and Amersham Biosciences). Various grades and chemistry forms of Sepharose are available.

[0172] The particles, specifically the beads, of the devices described herein may be associated with a chemically reactive portion referred to herein as a linker. As used herein, the linker may be any chemical entity comprising any aggregate of atoms, including oligomeric and polymeric chains of any length, which can be bound to the particles at one end and to at least one scavenger, its derivative or analog at the other end.

[0173] In some embodiments, beads can associate with the linker via spacers or coatings present on the beads. Thus, the beads are first activated by association with the spacers / coatings ("activated beads") and then react with the linker. It should be noted that sometimes, if the spacers / coatings are directly bound to at least one scavenger, a linker may not be further required. Sometimes, the beads do not have functional groups that can bind to the linker, and spacers or coatings can be used.

[0174] Activated beads are obtained by pre-coating the beads with a suitable material having an active portion that enables bonding to the beads and / or to the linker and / or scavenger. In other words, the beads are pre-coated to contain reactive groups that enable covalent bonding to either the linker or the scavenger.

[0175] In some embodiments, the beads of the conjugate of the disclosed device may be activated, for example, by pre-coating with any coating material. Non-limiting examples of such materials include, for example, amino acids, proteins, epoxy, tosyl, carboxylic acids, and carboxylated polyvinyl alcohols. Where "pre-coating" is used, it should be understood as a preliminary step resulting in the coating of the beads with an active substance that enables covalent bonding (i.e., directly) or covalent bonding via at least one linker between the beads and the sulfonic acid. In some embodiments, the beads of the conjugate of the disclosed device are pre-coated with amino acids, peptides, or any derivatives thereof. The pre-coated magnetic beads may, for example, contain primary amines (-NH2), carboxyls (-COOH), sulfhydryls (-SH), or carbonyls (-CHO) as active groups. In some embodiments, the beads of the conjugate of the disclosed device are pre-coated to include a moiety that can react with primary or secondary amino groups. In some other embodiments, the magnetic beads are coated with polylysine.

[0176] As used herein, the term "linker" includes any spacers or pre-coatings present on the beads.

[0177] In some embodiments, the linker includes or is a chain of atoms, for example, a linear chain. In some embodiments, the linker includes at least one atom, at least four atoms, sometimes five atoms, sometimes ten atoms, sometimes twenty atoms, sometimes thirty atoms, and sometimes forty atoms. In some embodiments, the linker is a linear chain of 1 to forty atoms, or includes such a chain. In some embodiments, the linker is a linear chain of one atom, or includes such a chain. In some embodiments, the linker is a linear chain containing five atoms. In some embodiments, the linker is a linear chain containing fifteen atoms.

[0178] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads, and therefore the resin beads are an agarose resin that may contain about 2% to 10% agarose in some embodiments. Furthermore, in some embodiments, the resin beads may contain 3% to 9% agarose, and furthermore, in some embodiments, the resin beads may contain 4% to 8% agarose. According to any further specific non-limiting embodiments, the resin beads contain at least 4% agarose. In some other embodiments, the amount of agarose in the particles of the conjugate of the disclosed device is at least 5%, sometimes at least 6%.

[0179] In some embodiments, the conjugate of the device of the present disclosure includes particles having an average particle size of about 10 μm or less to about 500 μm or more. Specifically, these include particles of 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, and 500 μm or more. In some specific embodiments, the multiple conjugates include particles having an average particle size of at least 70 μm or less, sometimes at least 80 μm, sometimes at least 90 μm, sometimes at least 100 μm, sometimes at least 110 μm, sometimes at least 120 μm, sometimes at least 130 μm, sometimes at least 140 μm, and sometimes at least 150 μm. In some embodiments, the multiple conjugates of the disclosed device exhibit an average particle size of about 40 μm or less to about 170 μm or more.

[0180] The terms "average size" or "average diameter" refer to the arithmetic mean of the measured diameters, where the diameters are within ±25% of the mean. The average size of the particles can be measured by any method known in the art. In certain embodiments, the size of the resin beads is 40–170 μm, and the average size is approximately 80–100 μm. Sometimes, the average size is 90 μm.

[0181] As described above, according to this embodiment, the present invention relates in particular to devices and systems for use in enabling the depletion of ammonia from biological fluids.

[0182] Referring to Figures 1 and 2, such a device according to a first embodiment of the subject matter of this disclosure, generally designated as 100, comprises a housing 200 and an active material 300 housed therein.

[0183] The housing 200 comprises an outer casing 230, an inlet end cap 222, and an outlet end cap 224. The housing 200 defines a longitudinal axis LA.

[0184] The outer casing 230 extends longitudinally between the inlet end 212 and the outlet end 214. In this example, at least, the casing is generally cylindrical.

[0185] The chamber 250 is defined between the outer casing 230, the inlet end 212, and the outlet end 214, and the chamber 250 provides a control volume CV that can be filled with the active material 300.

[0186] In this example at least, the inlet end cap 222 is configured to be sealed onto the inlet end 212, and the outlet end cap 224 is configured to be sealed onto the outlet end 214.

[0187] In this example at least, the inlet end cap 222, the outlet end cap 224, and the housing 230 are each made from a suitable medical-grade material, such as Terlux HD 2802 provided by Ineos, or Makrolon 2458 provided by Covestro.

[0188] In this example, at least, referring particularly to Figures 3(a) and 4(a) to 4(d), the inlet end cap 222 comprises an enlarged portion 222A, each having an inner diameter sufficient to allow each enlarged portion 222A to engage with its respective engaging portion 212A at the inlet end 212 in an overlapping manner. The free end 222B of each enlarged portion 222A comprises a substantially annular flat surface 222C.

[0189] Similarly, at least in this example, and particularly with reference to Figures 3(a), 5(a) to 5(d), the outlet end cap 224 comprises each enlarged portion 224A, which has an inner diameter sufficient to allow each enlarged portion 224A to engage with each engaging portion 214A at the outlet end 214 in an overlapping relationship. The free end 224B of each enlarged portion 224A comprises a substantially annular flat surface 224C.

[0190] In this example, at least with reference to Figures 3(a), 4(b), 4(d), 5(b), and 5(d), the inlet end cap 222 and the outlet end cap 224 each include female threaded walls 222X, 224X, which are complementary to the respective male threaded walls 232, 234 provided at the inlet end 212 and the outlet end 214, respectively. Optionally, an external sealing tape and / or an internal O-ring (not shown) may be provided for additional sealing between each inlet end cap 222 and / or outlet end cap 224 and the housing 230.

[0191] Furthermore, in this example at least, the inlet end cap 222 and the outlet end cap 224 are each configured as self-locking end caps to the outer casing 230, and allow the respective inlet end cap 222 and / or outlet end cap 224 to be sealed and locked to the casing 230 in a predetermined position.

[0192] For this purpose, at least in this example, also with reference to Figures 6 and 7, the device 100, in particular the housing 200, comprises a first self-locking device 280 configured to enable the self-locking of the inlet end cap 222 to the outer casing 230, and a second self-locking device 290 configured to enable the self-locking of the outlet end cap 224 to the outer casing 230.

[0193] Referring again to Figure 6, the first self-locking device 280 comprises a plurality of first wedge elements 282 provided on the inlet end cap 222, which work in cooperation with the first flange stop device 260 to provide self-locking of the inlet end cap 222 to the outer casing 230. In this embodiment, the inlet end cap 222 comprises two first wedge elements 282, but in alternative modifications of this example, the inlet end cap 222 may include one or three or more first wedge elements.

[0194] Each first wedge element 282 protrudes longitudinally away from its respective annular flat surface 222C, and furthermore, the first wedge elements 282 are arranged circumferentially at equal intervals from one another along their respective annular flat surfaces 222C.

[0195] In this example at least, each first wedge element 282 is in the form of a right-angle wedge and comprises each first wedge edge 283 and each second wedge edge 284 that intersect at each wedge vertex 285. The wedge vertex 285 is at a first wedge height WH1 with respect to the annular flat surface 222C. Each first wedge element also has a first base dimension BD1 in the annular flat surface 222C.

[0196] The first wedge edge 283 is inclined at an acute angle α with respect to each annular flat surface 222C. In this example at least, the angle α is significantly smaller than 90°, for example, in the range of about 5° to about 30°, for example, about 20°.

[0197] The second wedge edge 284 is inclined approximately perpendicular to each of the annular flat surfaces 222C. As will be made clearer herein, the second wedge edge 284 cooperates with the first flange stopper 260 to enable the inlet end cap 222 to self-lock against the outer casing 230.

[0198] The first flange stop device 260 is provided on the outer surface 232 of the outer casing 230 and includes a first annular flange 262 that is longitudinally spaced from the inlet end 212 by a first interval X1. The first annular flange has respective first annular surfaces 263 and respective second annular surfaces 264 that face each other. The first annular surface 263 faces in the direction toward the inlet end 212, and thus, the first annular surface 263 is spaced from the inlet end 212 by the first interval X1.

[0199] The first interval X1 is sufficient to ensure that when the inlet end cap 222 is fully engaged with the outer casing 230 (in at least this example, by screwing the inlet end cap 222 onto the outer casing 230), the respective annular flat surfaces 222C at the respective free ends 222B abut against the annular surface 263.

[0200] The first flange stop device 260 further includes a plurality of first stop elements 268 corresponding to the plurality of first wedge elements 282. Thus, in at least this example, the first flange stop device 260 includes two first stop elements 268 corresponding to the two first wedge elements 282.

[0201] In at least this embodiment, each first stop element 268 is in the form of a respective abutment surface 268A provided on the first annular flange 262. Thus, the first annular flange 262 includes a notch 267 corresponding to the first wedge element 282, and each notch 267 has a circumferential length and an axial depth that are at least equal to the first base dimension BD1 and the first wedge height WH1 of the respective first wedge element 282, respectively, to allow the respective first wedge element 282 to be received therein, and a respective abutment surface 268A for abutting against the respective second wedge edge 284.

[0202] Thus, when the inlet end cap 222 is screwed in the engagement rotation direction to the first inlet end 212 of the outer casing 230, finally the first wedge element 282 abuts against the first annular surface 263. As the inlet end cap 222 is further screwed onto the first inlet end 212 of the outer casing 230, the portions of the first wedge element 282 and / or the first annular flange 262 in contact therewith are slightly deformed until each first wedge element 282 is snap-fitted into each notch 267 through each first wedge edge 283. Thereafter, each second wedge edge 284 abuts in contact with each abutment surface 268A, preventing relative rotation in the disengagement direction between the inlet end cap 222 and the outer casing 230.

[0203] In an alternative variation of this embodiment, the first flange stop device 260 can be of a different form. For example, the first flange 262 can be replaced with a plurality of mechanical stops each including a boss projecting radially from the outer casing 230. Each such mechanical stop corresponds to a different one of the first wedges 282 and is located on the outer surface of the outer casing 230 at a respective position corresponding to the position of each first wedge element 282 when the inlet cap 222 is fully screwed to a predetermined position. Each such boss has a respective abutment surface for abutting against each second wedge edge 284.

[0204] Referring again to FIG. 7, the second self-locking device 290 includes a plurality of second wedge elements 292 provided in the outlet end cap 224 that cooperate with the second flange stop device 270 to provide self-locking of the outlet end cap 224 to the outer casing 230. In this embodiment, the outlet end cap 224 includes two second wedge elements 292, but in an alternative variation of this example, the outlet end cap 224 can include one or more than three second wedge elements.

[0205] Each second wedge element 292 protrudes longitudinally away from its respective annular flat surface 224C, and furthermore, the second wedge elements 284 are arranged circumferentially at equal intervals from one another along their respective annular flat surfaces 224C.

[0206] In this example at least, each second wedge element 292 is in the form of a right-angle wedge and comprises each first wedge edge 293 and each second wedge edge 294 that intersect at each wedge vertex 295. The wedge vertex 295 is at a second wedge height WH2 with respect to the annular flat surface 224C. Each second wedge element 292 also has a second base dimension BD2 in the annular flat surface 224C.

[0207] Each first wedge edge 293 is inclined at an acute angle β with respect to its respective annular flat surface 224C. In this example at least, the angle β is significantly smaller than 90°, for example, in the range of about 5° to about 30°, for example, about 20°.

[0208] Each second wedge edge 294 is inclined at approximately a right angle to its respective annular flat surface 224C. As will be made clearer herein, the second wedge edges 294 cooperate with the second flange stopper 270 to enable the outlet end cap 224 to self-lock against the outer casing 230.

[0209] The second flange stop device 270 is provided on the outer surface 232 of the outer casing 230 and comprises each first annular flange 272 longitudinally spaced by a second distance X2 from the outlet end 214. Each second annular flange 272 has a first annular surface 273 and a second annular surface 274 facing the opposite side. The first annular surface 273 faces toward the outlet end 214, and therefore each first annular surface 273 is spaced by a second distance X2 from the outlet end 214.

[0210] The second gap X2 is sufficient to ensure that when the outlet end cap 224 is fully engaged with the outer casing 230 (at least in this example by screwing the outlet end cap 224 against the outer casing 230), each annular flat surface 224C at each free end 224B is in contact with the annular surface 273.

[0211] The second flange stop device 270 further comprises a plurality of second stop elements 278 corresponding to a plurality of second wedge elements 292. Thus, at least in this example, the second flange stop device 270 comprises two second stop elements 278 corresponding to two second wedge elements 292.

[0212] In this embodiment at least, each second stop element 278 is in the form of a contact surface 278A provided on the second annular flange 272. Thus, the second annular flange 272 is provided with notches 277 corresponding to the second wedge elements 292, each notch 277 having a circumferential length and axial depth at least equal to the second base dimension BD2 and second wedge height WH2 of each second wedge element 292, and a contact surface 278A for contacting each second wedge edge 294, in order to accommodate each second wedge element 292 therein.

[0213] Therefore, as the outlet end cap 224 is screwed onto the outlet end 214 of the outer casing 230 in the engagement rotational direction, the second wedge elements 292 eventually come into contact with their respective first annular surfaces 273. As the outlet end cap 224 is further screwed onto the outlet end 214 of the outer casing 230, the second wedge elements 292 and / or the portion of the second annular flange 272 in contact with them deform slightly until each second wedge element 292 snaps into its respective notch 277 via its respective first wedge edge 293. Subsequently, each second wedge edge 294 comes into contact with its respective contact surface 278A, preventing relative rotation between the outlet end cap 224 and the outer casing 230 in the disengagement direction.

[0214] In alternative modifications of this embodiment, the second flange stopper 270 can be in a different form, for example, the second annular flange 272 can be replaced, for example, with a plurality of mechanical stoppers, each including a boss projecting radially from the outer casing 230. Each of these mechanical stoppers corresponds to one of the second wedge elements 292 and is located on the outer surface of the outer casing 230 at a position corresponding to the position of each second wedge element 292 when the outlet cap 224 is fully screwed into place. Each of these bosses has a contact surface for contacting each second wedge edge 294.

[0215] However, alternative variations of this example can provide different configurations for sealing the inlet end cap 222 and / or outlet end cap 224 to the casing 230.

[0216] Therefore, the inlet end cap 222 and / or outlet end cap 224 according to at least this embodiment facilitate the process of filling the control volume CV with the active material 300. One of the inlet end cap 222 and the outlet end cap 224 is sealed to the casing 230, leaving the other outlet end 214 or inlet end 212 open, respectively. The chamber 250 can then be filled with the desired amount of active material 300 through the open outlet end 214 or inlet end 212. The chamber 250 can then be closed by sealing the outlet end cap 224 or the inlet end cap 222 to the open outlet end 214 or inlet end 212, respectively, which can typically be done manually, without requiring special equipment, and can be domed in a simple manner that does not interfere with or damage the active material 300 in the control volume CV.

[0217] Referring particularly to Figure 1, in this embodiment at least, the device 100 includes a fluid inlet port 210 and a fluid outlet port 220. However, in alternative modifications of this embodiment, each device may have two or more fluid inlet ports and / or two or more fluid outlet ports. In either case, the fluid inlet port 210 and the fluid outlet port 220 are in fluid communication with the chamber.

[0218] In this example at least, the fluid inlet port 210 is provided on the inlet end cap 222, and the fluid outlet port 220 is provided on the outlet end cap 224.

[0219] Referring again to Figure 2, in this example at least, the device further comprises a first barrier member 310 at the inlet end 212 and a second barrier member 320 at the outlet end 214.

[0220] Each of the first barrier member 310 and the second barrier member 320 is configured to allow a unidirectional flow of fluid, particularly liquid plasma, through its respective barrier member, but to block a unidirectional flow of fluid, particularly liquid plasma, through its respective barrier member. Thus, each of the first barrier member 310 and the second barrier member 320 acts as its own unidirectional valve.

[0221] The first barrier member 310 and the second barrier member 320 are oriented within the device 100 to allow fluid flow, particularly liquid plasma flow, through the device 100 from the fluid inlet port 210 to the fluid outlet port 220, and at the same time to block backflow through the device 100 from the fluid outlet port 220 to the fluid inlet port 210.

[0222] Referring particularly to FIGS. 2 and 8, at least in this example, the first barrier member 310 is provided within the first barrier member assembly 319 and includes a membrane member 312 in the form of a disk made of a suitable medically compatible material such as, for example, polyethersulfone (PES) material, having a pore size of, for example, 15 μm, a thickness of, for example, 145.7 μm, and a diameter of about 44.5 mm. In the first barrier member assembly 319, the membrane member 312 is fixedly clamped between respective first rings 313 and respective second rings 314 and is housed within an annular gasket member 315 having a U-shaped cross-section. Referring also to FIG. 4(b), the enlarged portion 222A includes an internal shoulder 222D located between respective threaded walls 222X and the fluid inlet port 210, within which the first barrier member assembly 319 is mounted.

[0223] Similarly, referring particularly to FIGS. 2 and 9, at least in this example, the second barrier member 320 is provided within the second barrier member assembly 329 and includes a membrane member 322 in the form of a disk made of a suitable medically compatible material such as, for example, polyethersulfone (PES) material, having a pore size of, for example, 15 μm, a thickness of, for example, 145.7 μm, and a diameter of about 44.5 mm. In the second barrier member assembly 329, the membrane member 322 is fixedly clamped between respective first rings 323 and respective second rings 324 and is housed within an annular gasket member 325 having a U-shaped cross-section. Referring also to FIG. 5(b), the enlarged portion 224A includes an internal shoulder 224D located between respective threaded walls 224X and the fluid outlet port 220, within which the second barrier member assembly 329 is mounted.

[0224] In this example and alternative modifications of other examples, the barrier member may include, for example, a filter comprising a fiber or plastic substrate on which a ligand is conjugated, the ligand being conjugated to the fiber or plastic substrate, or may include, for example, other suitable membranes, such as a unidirectional membrane that allows bodily fluids to flow in one direction but not in the opposite direction.

[0225] Referring particularly to Figure 3(c), the control volume CV is enclosed and bounded by the first barrier member 310, the second barrier member 320, and the inner surface 235 of the outer housing casing 230.

[0226] In this example, at least, referring particularly to Figure 3(a), the housing 200 has a longitudinal length L1 of approximately 200 mm to approximately 210 mm, for example, 205 mm.

[0227] In this example at least, the housing 200 has an outer diameter D1 of approximately 40 mm to 50 mm, for example, 48.8 mm.

[0228] Referring to Figure 3(c), in this example at least, the chamber 250, in particular the control volume CV, has a longitudinal length L2 of about 200 mm to about 210 mm, for example 205 mm, and a diameter D2 of about 40 mm to about 45 mm, for example 42.8 mm.

[0229] In this example at least, the chamber 250 has a control volume CV of approximately 257 ml to 326 ml, for example, 306 ml, for accommodating the active substance 300.

[0230] According to this aspect of the subject matter of the present disclosure, with reference to Figure 10, also provided is a system 700 for enabling the depletion of ammonia from a biological fluid, comprising at least one device 100, an apheresis machine 900 (including a pool or blood mixture reservoir 890 and a separation system 870 including, for example, a centrifuge and a pump), and a conduit system 800.

[0231] The apheresis machine 900 is configured to receive blood from the body of the person requiring it (referred to herein as BD) via a conduit system 800, and to separate the received blood into its various components, namely plasma, platelets, leukocytes, and erythrocytes. Many examples of commercially available apheresis machines are known, such as the Spectra Optia Apheresis System by Terumo BCT. The apheresis machine 900 is also configured to return the treated blood to the body of the person requiring it via the conduit system 800 after treatment via device 100.

[0232] In this example at least, the blood mixing reservoir 890, which is integrated with the apheresis machine 900, is configured to receive plasma treated by device 100 and blood products (e.g., platelets, leukocytes, and erythrocytes, as well as some original plasma) separated from the plasma by the separation system 870 of the apheresis machine 900. The blood mixing reservoir 890 is also configured to allow the received treated plasma and blood products to be mixed to provide treated blood.

[0233] The conduit system 800 includes a first conduit 810 that provides selective fluid communication between the apheresis machine 900 and the body BD of the subject requiring it, enabling blood to flow from the body BD of the subject requiring it to the apheresis machine 900.

[0234] The conduit system 800 includes a second conduit 820 that provides fluid communication from the plasma outlet 910 of the apheresis machine 900 to the fluid inlet port 210 of the device 100, allowing plasma separated from the blood by the apheresis machine 900 to flow into the device 100.

[0235] The conduit system 800 includes a third conduit 830 via port 920 that provides fluid communication from the fluid outlet port 220 of device 100 to the blood mixing reservoir 890 of the apheresis machine 900, allowing the treated plasma treated by device 100 to flow into the blood mixing reservoir 890.

[0236] The conduit system 800 includes a fourth conduit 840 (within the apheresis machine 900) that provides fluid communication from the blood product outlet of the separation system 870 of the apheresis machine 900 to the blood mixing reservoir 890, allowing other products separated from the plasma by the separation system 870 of the apheresis machine 900 to flow into the blood mixing reservoir 890.

[0237] The conduit system 800 comprises a fifth conduit 850 that provides selective fluid communication between the blood mixing reservoir 890 of the apheresis machine 900 and the body BD of the subject requiring it, enabling the treated blood to flow from the blood mixing reservoir 890 of the apheresis machine 900 to the body BD of the subject requiring it.

[0238] Therefore, during the operation of system 700, system 700 is coupled to the body BD of the object requiring it via the conduit system 800, particularly via the first conduit 810 and the fifth conduit 850.

[0239] A suitable priming procedure is used to prime the system 700 with a suitable fluid, such as saline solution, before coupling the system 700 to the body BD of the target that requires it.

[0240] The apheresis machine 900 is operated to separate the incoming blood from the body BD of the person requiring it into plasma and blood products. The plasma is sent to the device 100 via a second conduit 820, and the other blood products separated by the apheresis machine 900 are sent to its blood mixture reservoir 890 via a fourth conduit 840.

[0241] The plasma is treated within device 100, and the treated plasma is sent via a third conduit 830 into the blood mixing reservoir 890 of the apheresis machine 900.

[0242] Subsequently, the treated blood is delivered from the blood mixing reservoir 890 of the apheresis machine 900 to the body of the person who needs it, via the fifth conduit 850.

[0243] In an alternative modification of this embodiment, for example, referring to Figure 11, the blood mixing reservoir 890 is separate from the apheresis machine 900, and the blood mixing reservoir 890 is connected to the apheresis machine 900, the device 100, and the body BD via separate fourth conduit 840, third conduit 830, and fifth conduit 850, respectively.

[0244] It should be noted that in alternative modifications of these embodiments, each system 700 may include a plurality of such devices 100, for example, batteries for such devices 100, which are coupled to each apheresis machine 900, blood mixing reservoir 890, and conduit system 800.

[0245] For example, in some such examples, referring to Figure 12, a plurality of such devices 100 (e.g., batteries 100A of such devices) can be connected in series with respect to each other, such that the fluid outlet port 220 of a first device is coupled (directly or via tubing) to the fluid inlet port 210 of the next device 100, and similar couplings are provided along the devices 100 arranged in series, with the fluid outlet port 220 of the last device 100 being coupled to a blood mixing reservoir 890 via a separate third conduit 830. Such a configuration can provide further treatment to the treated plasma before returning it to the body of the subject requiring it via a respective fifth conduit 850.

[0246] For example, in some other such examples, referring to Figure 13, multiple such devices 100 (e.g., in a battery 100B of such devices) can be connected in parallel to one another such that a first conduit 810 is simultaneously connected to the fluid inlet port 210 of all devices, for example, via a first manifold 825. Similarly, the fluid outlet ports 220 of all devices 100 are simultaneously connected to a third conduit 830, and therefore, for example, to a blood mixing reservoir 890 via a second manifold 835. Such a configuration can allow for the simultaneous treatment of blood at larger volumetric flow rates.

[0247] For example, in some other examples, referring to Figure 14, such multiple devices 100 (e.g., in the battery 100C of such a device) can be interconnected in both parallel and series, i.e., the devices are divided into groups 100G, the devices 100 within each group 100G are connected in series with each other, and the groups 100G are connected together in parallel. Each group 100G may include one, two, three, or more devices connected in series such that the fluid outlet port 220 of each upstream device is connected (directly or via tubing) to the fluid inlet port 210 of the next device 100.

[0248] In this example at least, the active substance 300 comprises at least one of a conjugate, a plurality of conjugates, or at least one composition comprising a conjugate or a plurality of conjugates. More specifically, the conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] -In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger is characterized by having the ability to capture or bind amines. In some optional embodiments, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0249] It should be understood that the body of the subject requiring such treatment refers to any mammalian subject requiring such treatment, as also referred to herein as BD in Figures 10-14. In some embodiments, this subject (which may also be referred to herein as a patient in some embodiments) is a subject having or exhibiting elevated blood ammonia levels, and / or suffering from any disorder and / or condition associated with elevated blood ammonia levels, such as hyperammonemia, and any of the conditions and disorders disclosed herein in relation to other embodiments.

[0250] In some embodiments, the device of the present disclosure may be used to deplete at least one amine from at least one liquid substance.

[0251] In some further specific embodiments, the amine depleted by the device of the Disclosure is ammonia. In some further embodiments, the liquid substance is mammalian body fluid. Thus, the device of the Disclosure is used to deplete ammonia from mammalian body fluid.

[0252] In some embodiments, the conjugate contained within the device is one of the conjugates defined in this disclosure.

[0253] In some specific embodiments, the conjugate of the device of the present invention has structural formula V. More specifically, the conjugate comprises particles covalently bonded to at least one linker containing a chain of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more carbon atoms, specifically 15 carbon atoms, covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10. In some embodiments, the liner comprises a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups, specifically 5, 6, 7, 8, 9, or 10 or more carbonyl groups.

[0254] In some further embodiments, the devices of the present disclosure are configured to accommodate at least about 50 ml to about 500 ml of the conjugates disclosed herein, or any multiple conjugates or compositions thereof, specifically about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, and 500 ml. In some further embodiments, the device of the Disclosure is configured to accommodate a conjugate disclosed herein with a volume of at least about 250–350 ml, specifically 270–300 ml.

[0255] To make it clearer herein, the device is configured to deplete at least one ammonia from a mammalian body fluid (e.g., human plasma and / or human whole blood and / or other mammalian plasma and / or other mammalian whole blood) as an example of treating mammalian body fluids. More specifically, the device disclosed herein is configured to deplete, reduce, and distribute ammonia from body fluids.

[0256] The term “distribution” with respect to a target compound, specifically at least one amine, and more specifically ammonia, refers to separating ammonia from the remainder of a liquid substance, specifically from blood fluid, to provide ammonia-free body fluid or any other liquid substance. Thus, the term “distribution” encompasses the depletion and removal of at least one amine, and more specifically ammonia, from a liquid substance, specifically body fluid. As used herein, the terms “deplete” or “exhaust” are defined as removing ammonia from a liquid substance, specifically body fluid, to such an extent that a liquid substance, specifically body fluid, is obtained in which ammonia is depleted or reduced. More specifically, the terms “removal” or “depletion” as used herein, by either the distribution or capture of at least one amine, specifically ammonia, means the restriction, reduction, decrease, or decrease of at least about 1% to 100%, about 5% to 95%, about 10% to 90%, about 15% to 85%, about 20% to 80%, about 25% to 75%, about 30% to 70%, about 35% to 65%, about 40% to 60%, or about 45% to 55% of the amount of at least one amine, specifically ammonia, in a liquid substrate or body fluid. Such restriction, delay, reduction, decrease, or decrease in the amount of at least one amine, specifically ammonia, in a liquid substance, specifically body fluid, also means at least about 1%, 2%, 3%, 4%, 5%, 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%, 44% These are %, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 100%.

[0257] In some further embodiments, the devices of the disclosed herein are adapted to deplete, remove, and reduce at least one amine, specifically ammonia, from at least one liquid substance of any volume. More specifically, in some embodiments, the disclosed devices are adapted to deplete at least about 100 ml of body fluid from at least about 10 liters of body fluid, in particular 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2 It is suitable for depleting ammonia from 700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, and 5000 ml or more, specifically, from 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, and 10 liters of body fluids.

[0258] Further aspects provided by this disclosure relate to batteries for use in depleting ammonia from mammalian bodily fluids, including a plurality of devices as defined by this disclosure.

[0259] Further embodiments relate to an external device comprising at least one conjugate, or at least one device comprising a conjugate. In some embodiments, the external device may be connected to such at least one device or a battery of the device. In more specific embodiments, the conjugate of the external device of the present disclosure may comprise a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10. More specifically, the scavenger A is characterized by having the ability to scavenge or bind an amine, and optionally the amine is at least one of methylamine, dimethylamine, or trimethylamine. In some further embodiments, the device contained within or connected to an external device is - A housing may have at least one fluid inlet port and at least one fluid outlet port. - The housing includes at least one chamber, which defines a reference volume that is in fluid communication with at least one fluid inlet port and at least one fluid outlet port. The reference volume accommodates at least one conjugate, a plurality of conjugates, or at least one composition comprising a conjugate or a plurality of conjugates.

[0260] In some embodiments, the conjugate, multiple conjugates or compositions, devices and batteries used in the external device are as defined herein.

[0261] In some embodiments, the external devices of this disclosure are applicable to use in depleting ammonia from mammalian body fluids.

[0262] In some further embodiments, the extracorporeal device of the Disclosure is adapted to deplete, remove, and reduce at least one amine, specifically ammonia, from at least one liquid substance of any volume. More specifically, in some embodiments, the disclosed extracorporeal device is particularly adapted to deplete ammonia from at least about 100 ml of body fluid to at least about 10 liters of body fluid, specifically about 2 to 3 liters of body fluid.

[0263] In a further embodiment, the present invention relates to a conjugate having structural formula I, comprising particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10. In some embodiments, the scavenger A is characterized by having the ability to scavenge or bind amines. As described above, in some embodiments, the linker contains 5 to 15 carbon atoms. In some embodiments, the length of one carbon atom is about 1.5 angstroms, so therefore, in some embodiments, the length of the linker may be in the range of 7.5 angstroms or less to 22.5 angstroms or more. In some further embodiments, the linker further contains 5 to 10 carbonyls. Since each carbonyl can be about 1.3 angstroms in length, this length may be in the range of about 6.5 angstroms or less to about 13 angstroms or more.

[0264] In other words, this disclosure is in three parts, namely -particles and, -Linker and, - Provides a conjugate containing a scavenger.

[0265] The three parts are bonded together so that the linker connects the particles and the trapping agent.

[0266] The linker of the present invention generally comprises two groups, the first of which comprises a linear alkane containing n carbon atoms and a group of m covalently bonded carbonyl groups.

[0267] In some embodiments, the linear alkane of the linker of the conjugate of the present disclosure is saturated or unsaturated.

[0268] In some embodiments, the linear alkane group may be saturated, while in other embodiments, the group may be unsaturated.

[0269] In embodiments where the linear alkane group is unsaturated, the chain may contain 1 to 3 double bonds.

[0270] The scavenger portion, as indicated herein as A, may include any agent having the ability to “scavenge” or bind amines.

[0271] In the context of this disclosure, the term amine refers to any compound or functional group containing at least one basic nitrogen atom having at least one lone pair of electrons. Examples of amines according to this disclosure include any primary, secondary, and tertiary amines having a molecular weight (MW) of at least 17 to a maximum of 70 daltons.

[0272] In some embodiments, the amine is an alkylamine, dialkylamine, or trialkylamine, and the MW of such amine is 17 to 70 daltons.

[0273] In some other embodiments, the amine is selected from methylamine, dimethylamine, or trimethylamine.

[0274] In certain embodiments, the amine is ammonia.

[0275] The linker of the present invention has a linear bond at the m-th carbonyl group. [ka] via, or another short alkane chain [ka] The scavenger is covalently bonded to the scavenger via a bond, where X is an integer between 1 and 3.

[0276] In some embodiments, the scavenger can be any ion exchange material. More specifically, ammonia can bind to a cation exchanger because it is cationic at physiological pH. Other alternatives included in the present invention include NHS and epoxy.

[0277] In some embodiments, the scavenger is an acid.

[0278] In some embodiments, the acid is a strong acid capable of capturing the amine.

[0279] In some embodiments, the amine is as defined above.

[0280] In some other embodiments, the amine is ammonia.

[0281] In the context of the disclosures provided herein, the term “strong acid” is any acid having a pKa value less than 1.

[0282] Sometimes the pKa is lower than 0, sometimes lower than (-1), sometimes lower than (-2), sometimes lower than (-3), sometimes lower than (-4), sometimes lower than (-5), sometimes lower than (-6), sometimes lower than (-7), sometimes lower than (-8), and sometimes lower than (-9).

[0283] In some specific embodiments, the acid is selected from the group consisting of chloric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, hydroiodic acid, their analogs and derivatives.

[0284] In certain embodiments, the acid is sulfuric acid or a derivative thereof.

[0285] A derivative of a sulfonic acid can be any molecule having the following general formula: [ka] In the formula, R is an organoalkyl or aryl group.

[0286] In the embodiment, the sulfonic acid derivative is selected from taurine, PFOS, p-toluenesulfonic acid, and coenzyme M.

[0287] In some embodiments, R is -H.

[0288] In most common terms, the length of a linear alkane determines the specificity of the conjugate. Linkers that are too long trap nonspecific / undesirable molecules such as proteins and amino acids (because they contain amino groups). Short linkers reduce the conjugate's ability to trap ammonia and ammonium cations.

[0289] Therefore, in some embodiments, the length (n) of the linear alkane is 5 to 20 carbon atoms, specifically 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 1 to 20, 12 to 20, 13 to 20, 14 to 20, and 15 to 20. In some further embodiments, the length (n) of the linear alkane is sometimes 10 to 15, sometimes 12 to 15, sometimes 13 to 15, and sometimes 14 to 15. In some specific embodiments, the length (n) of the linear alkane is 5 or less, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or greater. In certain non-limiting embodiments, n is 15.

[0290] While we do not wish to be bound by theory or mechanism, the carbonyl moiety provides a suitable bulk to prevent the binding of amino acids and peptides to the acidic moiety of the conjugate. Surprisingly, the inventors of this disclosure have found that 5 to 10 carbonyl groups bound together provide a suitable bulk to prevent larger molecules from being trapped by the acidic moiety of the conjugate.

[0291] Accordingly, in embodiments, the conjugate of the Disclosure (as referred to herein by all formulas and embodiments) comprises about 5 to 10 carbonyl groups (m), specifically 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 6 to 8, 6 to 7, 7 to 10, 7 to 9, 7 to 8, 5 to 10, and 8 to 9. More specifically, 5, 6, 7, 8, 9, or 10 carbonyl groups. In certain non-limiting embodiments, m is 5, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 5th carbonyl group. In certain non-limiting embodiments, m is 6, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 6th carbonyl group. In certain non-limiting embodiments, m is 7, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 7th carbonyl group. In certain non-limiting embodiments, m is 8, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 8th carbonyl group. In certain non-limiting embodiments, m is 9, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 9th carbonyl group. In certain non-limiting embodiments, m is 10, and according to such embodiments, the sulfonic acid covalently bonded to the m-th carbonyl group means the sulfonic acid covalently bonded to the 10th carbonyl group.

[0292] In certain embodiments, it should be understood that the conjugates of the present disclosure may include any bonding of any number (m) of carbonyl groups to any number of linear alkanes (n).

[0293] In another embodiment of the present invention, a conjugate is provided comprising particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and an acid A covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula II. [ka] In the equation, x ranges from 0 to 3.

[0294] When x is 0, the m-th carbonyl group is directly bonded to the acid.

[0295] In some further embodiments, the present invention provides a conjugate comprising particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. [ka] In the equation, x ranges from 0 to 3.

[0296] In some embodiments, x is between 0 and 2, and sometimes between 0 and 1. Sometimes x is 1, and sometimes x is 0.

[0297] When x is 0, the m-th carbonyl group is directly bonded to the acid.

[0298] In some embodiments, the conjugate of the present disclosure is configured to act as an amine trap and exhibit an amine neutralization reaction. In more specific embodiments, the amine is ammonium.

[0299] Furthermore, in some embodiments, the linker portion of the conjugate of the present disclosure is connected to the particles via any suitable functional group that enables the particles to be connected to a linear alkane.

[0300] Without being bound by theory or reaction mechanism, the conjugate of the present invention acts as an amine trap exhibiting a neutralization reaction of one amine as defined above for each acid scavenger in the following manner: [ka] In the formula, -H represents the free hydrogen atom of the acid, and (:) represents the free electron of the amine.

[0301] In embodiments where the acid is a sulfonic acid and the amine is ammonia, the proton (H + )teeth, [ka] The two free electrons of ammonia are donated to form an ionic bond between the conjugate acid and the conjugate base.

[0302] The linker portion of the disclosure herein may be attached to the particles via any group known in the art that enables the particles to be attached to a linear alkane.

[0303] In one possible embodiment, the particles and the linker are covalently bonded.

[0304] In another optional embodiment, the bond is a covalent bond via an amino group, as shown in formula IV. [ka]

[0305] Furthermore, in some other embodiments, the present invention intends a conjugate having structural formula V, where n is 15, m is an integer between 5 and 10, x is 0, and A is a sulfonic acid. [ka]

[0306] The present invention provides at least one conjugate. As used herein, a conjugate refers to a compound constructed from certain elements (components), including at least one particle, at least one linker, and at least one scavenger, specifically, in some embodiments, an ammonia scavenger which may be a sulfonic acid or any derivative or analog thereof, all of which associate therewith. While this application refers to "at least one particle," it should be noted that any solid support applicable to any of the claimed conjugates is encompassed herein.

[0307] Any one of the conjugates of the subject matter of this disclosure, or any composition thereof, may also be referred to as a composition. In the most common terminology, “composition of substance” as well as “conjugate” are both used interchangeably and refer to an association of at least one particle, at least one linker, and at least one scavenger, derivative thereof, or analogue thereof, which may result in properties attributable to the composition of substance (or conjugate) as a whole, but not to any one of the components of the conjugate in their separate states, as detailed below.

[0308] In some embodiments, any one of the conjugates of the subject matter of this disclosure comprises the association of at least one particle with at least one chemically reactive moiety which is a linker, and the association of at least one linker with at least one scavenger, specifically a sulfonic acid and its derivatives or analogs, such that the linker is located between the particle and the scavenger, its derivatives or analogs, and thus associates with the particle at one end (in one arm) and with the scavenger, its derivatives or analogs at the other end (in a second different arm).

[0309] In some embodiments, the scavenger, specifically sulfonic acid and its derivatives, specifically and selectively binds to a particular target, in this case at least one amine, such as ammonia, enabling the effective capture, immobilization, distribution, and removal of ammonia from liquid substances, specifically body fluids.

[0310] As used herein, the term “association” or any linguistic variation thereof means a chemical or physical force that holds two entities together (e.g., a particle and a linker). Such a force may be any type of chemical or physical bonding interaction known to those skilled in the art.

[0311] Non-limiting examples of such association interactions include covalent bonds, ionic bonds, coordination bonds, complex formation, hydrogen bonds, van der Waals bonds, and hydrophobic-hydrophilic interactions. Therefore, the association / conjugation of a linker with at least one particle, and the association / conjugation of a linker with a scavenger, may be via any chemical bond, including covalent bonds, electrostatic interactions, acid-base interactions, van der Waals interactions, etc. As can be understood, the association of a particle with a linker, and the association of a linker with a scavenger, its derivatives, or analogues, may be the same or different, as will be further detailed below.

[0312] The particles of the present invention may include any polymer particles that can be bonded to the linker of the present invention.

[0313] In some embodiments, the particles are resin beads.

[0314] As used herein, the term "particle" refers to a part of a substance having a surface to which it can be bonded to chemical or biological compounds, small molecules or large molecules, which can be bonded either via covalent or non-covalent bonds. Particles may include porous materials. Particles may be, for example, "spherical" (generally referring to a substantially (almost) round ball shape) or "non-spherical" (having an "elongated" shape with defined long and short axes). Non-limiting examples of particles include beads such as polysaccharide beads, glass beads, cotton beads, plastic beads, nylon beads, latex beads, magnetic beads, paramagnetic beads, superparamagnetic beads, starch beads, etc., as well as at least one of silicon beads, PTFE beads, polystyrene beads, gallium arsenide beads, gold beads, or silver beads. In some embodiments, particles are agarose beads, optionally, beads containing different degrees of crosslinking at different percentages of the material (agarose).

[0315] Therefore, agarose beads encompass beads containing agarose of various degrees of crosslinking, such as beads referred to as Sepharose beads. In some embodiments, the beads include agarose beads. In some embodiments, the beads include Sepharose beads. In some embodiments, the conjugates include a combination of particles containing agarose beads and Sepharose beads. It should be noted that according to this disclosure, particles that are either agarose beads or Sepharose beads are considered to be two different conjugates having different particles.

[0316] The particles described herein, specifically the beads, may associate with a chemically reactive portion referred to herein as a linker. As used herein, the linker may be any chemical entity comprising any aggregate of atoms, comprising oligomeric and polymeric chains of any length, which may be bound at one end to a particle and at the other end to at least one scavenger, its derivative or analogue thereof.

[0317] In some embodiments, beads can associate with the linker via spacers or coatings present on the beads. Thus, the beads are first activated by association with the spacers / coatings ("activated beads") and then react with the linker. It should be noted that sometimes, if the spacers / coatings are directly bound to at least one scavenger, a linker may not be further required. Sometimes, the beads do not have functional groups that can bind to the linker, and spacers or coatings can be used.

[0318] Activated beads are obtained by pre-coating the beads with a suitable material having an active portion that enables bonding to the beads and / or to the linker and / or scavenger. In other words, the beads are pre-coated to contain reactive groups that enable covalent bonding to either the linker or the scavenger.

[0319] In some embodiments, the beads may be activated by pre-coating with any coating material, for example. Non-limiting examples of such materials include, for example, amino acids, proteins, epoxy, tosyl, carboxylic acids, and carboxylated polyvinyl alcohols. When referring to “pre-coating,” it should be understood as a preliminary step resulting in the coating of the beads with an active substance that enables covalent bonding (i.e., direct) or covalent bonding via at least one linker between the beads and the sulfonic acid. In some embodiments, the beads are pre-coated with amino acids, peptides, or any derivatives thereof. The pre-coated magnetic beads may, for example, contain primary amines (-NH2), carboxyls (-COOH), sulfhydryls (-SH), or carbonyls (-CHO) as active groups. In some embodiments, the beads are pre-coated to include a moiety that can react with primary or secondary amino groups. In some other embodiments, the magnetic beads are coated with polylysine.

[0320] As used herein, the term "linker" includes any spacers or pre-coatings present on the beads.

[0321] In some embodiments, the linker includes or is a chain of atoms, for example, a linear chain. In some embodiments, the linker includes at least one atom, at least four atoms, sometimes five atoms, sometimes ten atoms, sometimes twenty atoms, sometimes thirty atoms, and sometimes forty atoms. In some embodiments, the linker is a linear chain of 1 to forty atoms, or includes such a chain. In some embodiments, the linker is a linear chain of one atom, or includes such a chain. In some embodiments, the linker is a linear chain containing five atoms. In some embodiments, the linker is a linear chain containing fifteen atoms.

[0322] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads, and therefore the resin beads are an agarose resin that may contain about 2% to 10% agarose in some embodiments. Furthermore, in some embodiments, the resin beads may contain 3% to 9% agarose, and further, in some embodiments, the resin beads may contain 4% to 8% agarose. In some embodiments, the resin beads contain at least 4% agarose.

[0323] In some other embodiments, the amount of agarose in the particles is at least 5%, sometimes at least 6%.

[0324] In some embodiments, the conjugate of the present disclosure includes particles having an average particle size of about 10 μm or less to about 500 μm or more. Specifically, these include particles of 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, and 500 μm or more. In some specific embodiments, the multiple conjugates include particles having an average particle size of at least 70 μm or less, sometimes at least 80 μm, sometimes at least 90 μm, sometimes at least 100 μm, sometimes at least 110 μm, sometimes at least 120 μm, sometimes at least 130 μm, sometimes at least 140 μm, and sometimes at least 150 μm. In some embodiments, the multiple conjugates exhibit an average particle size of approximately 40 μm or less to approximately 170 μm or more.

[0325] The terms "average size" or "average diameter" refer to the arithmetic mean of the measured diameters, where the diameter is within ±25% of the average. The average size of the particles can be measured by any method known in the art. In certain embodiments, the size of the resin beads is 40–170 μm, and the average size is 80–100 μm. Sometimes, the average size is 90 μm.

[0326] In some embodiments, the multiple conjugates provided by this disclosure may be particularly applicable for use in depleting at least one amine from at least one liquid substance.

[0327] In some further embodiments, conjugate scavenger A among the plurality of conjugates of the present disclosure is particularly configured to scavenge at least one amine. In some embodiments, the amine is ammonia. In some further embodiments, the liquid substance is a mammalian body fluid. Thus, in some embodiments, the plurality of conjugates provided by the present disclosure are particularly applicable to use in depleting ammonia from a mammalian body fluid.

[0328] In some embodiments, the multiple conjugates provided by this disclosure may be particularly applicable for use in depleting at least one amine from at least one liquid substance.

[0329] Further aspects of the present disclosure relate to a plurality of conjugates or any composition comprising a plurality of conjugates. In more specific embodiments, each conjugate comprises a particle, at least one linker, and at least one scavenger A, or any derivative or analog thereof. More specifically, the conjugate of the present disclosure comprises a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10. In some embodiments, the scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0330] In some embodiments, a conjugate among the plurality of conjugates disclosed by the present invention or a conjugate in any composition is as defined herein.

[0331] In some embodiments, the multiple conjugates provided by this disclosure may be particularly applicable for use in depleting at least one amine from at least one liquid substance.

[0332] In some further embodiments, conjugate scavenger A among the plurality of conjugates of the present disclosure is particularly configured to scavenge at least one amine. In some embodiments, the amine is ammonia. In some further embodiments, the liquid substance is a mammalian body fluid. Thus, in some embodiments, the plurality of conjugates provided by the present disclosure are particularly applicable to use in depleting ammonia from a mammalian body fluid.

[0333] Further aspects of the present disclosure relate to a method for depleting at least one amine from a liquid substance. More specifically, the method comprises the following steps: In a first step (i), the liquid substance is subjected to an affinity depletion procedure specific to at least one amine. The next step (ii) comprises recovering the liquid depleted of at least one amine obtained in step (i). In some embodiments, the affinity depletion procedure comprises contacting the liquid substance with an effective amount of at least one conjugate, a plurality of conjugates, or a composition comprising a conjugate or a plurality of conjugates, or applying the liquid substance onto a device, battery, or external device comprising the conjugates of the present disclosure. In a more specific embodiment, each conjugate comprises a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0334] It should be understood that in certain embodiments, the conjugates of the Disclosure may include any combination of any number (m) carbonyl groups and any number of linear alkanes (n). Therefore, in some embodiments, the conjugates considered herein may include any mixture or combination of any conjugates in which 5 to 15 linear alkanes are bonded to 5 to 10 carbonyl groups.

[0335] In some embodiments, the liquid substance used in the methods of the present disclosure is a mammalian bodily fluid or any product thereof.

[0336] In some further embodiments, the method of the present invention is used to deplete at least one amine from any liquid substance. In some embodiments, the amine is ammonia. Thus, in some embodiments, the method of the present disclosure is for use in depleting ammonia from mammalian body fluids. As described above, the method of the present disclosure is adapted to deplete and reduce ammonia from at least about 0.5 liters to about 10 liters of body fluid, specifically about 2 to 3 liters of body fluid.

[0337] It should be noted that in some embodiments, any conjugate, multiple conjugates or compositions, devices and / or batteries used by the methods discussed herein are as defined by the present invention.

[0338] As described above, the method of the present invention includes an in vitro procedure. In some embodiments, the in vitro device is a cardiopulmonary bypass machine (CPB), and the in vitro device is a plasma exchange machine.

[0339] The term "extracorporeal" refers to medical procedures performed outside the body. For example, such extracorporeal procedures may relate to circulatory procedures, i.e., procedures in which blood is taken from the patient's circulation and a process is applied to the blood before it is returned to the circulation. All devices that transport blood outside the body are referred to as extracorporeal circuits. Examples of such circulatory procedures include, but are not limited to, apheresis, autologous transfusion, hemodialysis, hemofiltration, plasma exchange, extracorporeal carbon dioxide removal, extracorporeal cardiopulmonary resuscitation, extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass during open-heart surgery.

[0340] Cardiopulmonary bypass (CPB) is a technique that temporarily takes over the function of the heart and lungs during surgery to maintain blood circulation and oxygen levels in the patient's body. The CPB pump itself is often referred to as a cardiopulmonary bypass machine or simply a "pump." The cardiopulmonary bypass pump is operated by a perfusion technician. CPB is a form of extracorporeal circulation. Extracorporeal membrane oxygenation (ECMO) machines are generally used for long-term procedures.

[0341] An apheresis machine is a device that receives blood removed from the body of a person who needs it and separates it into its various components: plasma, platelets, white blood cells, and red blood cells.

[0342] A further aspect of the present invention relates to a method for depleting at least one amine from a bodily fluid of a subject requiring such depletion. More specifically, the method may involve contacting the bodily fluid with an effective amount of conjugates, a plurality of conjugates or compositions thereof, or in a device or battery containing conjugates, or alternatively, with an extracorporeal device containing or connected to a conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step includes recovering amine-free body fluid and, optionally, reintroducing this body fluid to the desired target.

[0343] In some further specific, non-limiting embodiments, the method may include the use of an in vitro procedure. More specifically, such a method may include the following steps: First, in step (i), the target bodily fluid is transferred to an extracorporeal device. The next step (ii) involves subjecting the body fluid to an affinity depletion procedure specific to at least one amine, which is performed before, during, or after the blood is transferred in or out of the device, thereby obtaining the extracorporeal body fluid of the subject from which at least one amine has been depleted. The next step (iii) includes reintroducing or returning the body fluid obtained in step (ii) to the target. As described above, the affinity depletion procedure includes contacting the target body fluid with an effective amount of conjugate, multiple conjugates, or a composition thereof contained within the extracorporeal device or within a device or battery connected to the extracorporeal device. Each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0344] In some embodiments, the conjugate, multiple conjugates or compositions, devices, batteries and apparatus used by the method of the present invention are any of those disclosed herein.

[0345] In some embodiments, the conjugate used by the method of the present disclosure has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0346] In some embodiments, the methods of the subject matter of this disclosure may be applicable to depleting ammonia from any liquid material or substance, specifically from body fluids. Body fluids, bodily fluids, or biofluids, as used herein, are the fluids within the body of a mammal, specifically the body of a human. In some embodiments, this term may refer to any body fluid, including blood, plasma, saliva, vaginal fluid, semen, urine, mucus, etc., but in the context of this disclosure, it refers to blood and plasma, as considered below. Average total body water is about 60% (60–67%) of total body weight, which is usually slightly lower in women (52–55%). The exact percentage of body fluids to body weight is inversely proportional to the percentage of body fat. The total water is divided in a 2:1 ratio into two fluid compartments: the intracellular fluid (ICF) compartment (also called space or volume) and the extracellular fluid (ECF) compartment (space, volume). 28 (28-32) liters are in the inner cells and 14 (14-15) liters are in the outer cells. The ECF compartment is divided in a 3:1 ratio into the interstitial fluid volume, which is the fluid outside both cells and blood vessels, and the vascular volume (also called vascular volume or plasma volume), which is the fluid inside the blood vessels. The interstitial fluid volume is approximately 12 liters, and the vascular volume is approximately 4 liters.

[0347] In some embodiments, the body fluid referred to herein is plasma. Plasma is the liquid component of blood released from blood cells, but retains the proteins and other components of whole blood in suspension. It constitutes approximately 55% of the body's total blood volume. This is the intravascular portion of the extracellular fluid, as discussed above. Plasma is composed mostly of water (up to 95% by volume), with important soluble proteins (6-8%) (e.g., serum albumin, globulin, and fibrinogen), glucose, coagulation factors, and electrolytes (Na). + Ca 2+ Mg 2+ , HCO3 - Cl - It contains hormones, carbon dioxide, and oxygen, among other things. Plasma has a viscosity of approximately 1025 kg / m³. 3 or having a density of 1.025 g / ml. Furthermore, in some embodiments, the body fluid useful in this disclosure may be serum that does not contain coagulation factors, i.e., plasma as considered herein.

[0348] In some embodiments, the methods of the subject matter of this disclosure may be applicable to deplete ammonia from a body fluid which may be at least one of whole blood, plasma, or blood-derived products.

[0349] In some specific embodiments, such blood-derived products may be at least one of whole blood, plasma, fresh frozen plasma (FFP), platelet-rich plasma (PRP), and cryoprecipitate.

[0350] It should be understood that in some embodiments, the methods of the subject matter of this disclosure may be carried out ex vivo or in vitro. More specifically, in bodily fluids that are no longer part of the human body.

[0351] This disclosure provides conjugates, devices, and methods for depleting ammonia from body fluids and thereby obtaining ammonia-depleted body fluids with reduced ammonia content. As used herein, “ammonia-depleted or reduced body fluid” or “ammonia-free body fluid” means that the preparations of the subject matter of this disclosure (according to some embodiments, prepared by treating body fluids such as blood, plasma, or blood products with an ammonia binder, specifically the devices and conjugates disclosed herein) exhibit a reduced, diminished, or attenuated amount of ammonia by about 50% to 100% compared to untreated blood or blood products. More specifically, compared to untreated blood or blood products, at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the ammonia initially or normally present in the body fluids, specifically blood or blood products, before depletion using the methods, devices and conjugates disclosed herein is removed from the preparations subject to this disclosure. In other words, the preparations subject to this disclosure may contain ammonia in amounts ranging from about 0.01% to about 50% of the amount of ammonia in other preparations or untreated blood or blood products, specifically blood, plasma, or blood products that have not been subjected to the conjugates, devices and methods disclosed herein. Specifically, this refers to ammonia levels of approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, and 70% or less compared to untreated blood or blood products.

[0352] As described above, body fluids, blood, plasma, or blood products treated by the methods of the subject matter of this disclosure exhibit reduced, decreased, or depleted amounts of ammonia. The terms “reduced” or “decreased” as used herein refer to body fluids such as blood, plasma, or blood products containing ammonia, blood or blood products not treated with the conjugates of the subject matter of this disclosure, blood of subjects suffering from conditions associated with high concentrations of ammonia, and, in some embodiments, about 1% to 99.9% compared to normal blood or blood products or commercially available blood products, specifically about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, and about 2%. Please understand that this relates to a reduction or decrease in the amount of at least one amine, specifically ammonia, in any of the following ranges: 0%-25%, approximately 25%-30%, approximately 30%-35%, approximately 35%-40%, approximately 40%-45%, approximately 45%-50%, approximately 50%-55%, approximately 55%-60%, approximately 60%-65%, approximately 65%-70%, approximately 75%-80%, approximately 80%-85%, approximately 85%-90%, approximately 90%-95%, approximately 95%-99%, or approximately 99%-99.9%, or even 100%. In other words, these formulations either show no ammonia or show at most minimally reduced amounts of ammonia compared to the amount of ammonia in untreated blood, plasma, or blood products or any other body fluids, specifically about 0.01% or less, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or less of ammonia. In some embodiments, body fluids, blood, plasma, or blood products treated by methods, conjugates, compositions, and devices, batteries, kits, or systems provided by the subject of this disclosure, showing the ammonia reduction as defined above or showing no ammonia, may be used for any therapeutic applications disclosed by the subject of this disclosure, as will be discussed later herein.

[0353] Furthermore, in some other specific embodiments, the subject matter of this disclosure may be used in vivo / ex vivo to deplete at least one ammonia from and / or in the bodily fluids of a subject requiring it.

[0354] Further aspects of this disclosure relate to methods for treating, preventing, remedying, improving, or inhibiting disorders or pathological conditions associated with elevated blood ammonia levels in subjects requiring such treatment, by depleting ammonia from the body fluids of subjects requiring such treatment.

[0355] More specifically, the therapeutic methods disclosed herein may involve contacting a body fluid to be treated with an effective amount of a conjugate, a plurality of conjugates or a composition thereof, or within a device or battery containing a conjugate, or alternatively, with an extracorporeal device containing or connected to a conjugate or device disclosed herein. It should be noted that each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group. [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and scavenger A is characterized by having the ability to capture or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step includes recovering amine-free body fluid and, optionally, reintroducing this body fluid into the treated subject.

[0356] In some further specific and non-limiting embodiments, the method may include the use of an in vitro procedure. More specifically, such a method may include the following steps: First, in step (i), the target bodily fluid is transferred to an extracorporeal device. The next step (ii) involves subjecting the body fluid to an affinity depletion procedure specific to at least one amine, which is performed before, during, or after the blood is transferred in or out of the apparatus, thereby obtaining the extracorporeal body fluid of the treated subject from which at least one amine has been depleted. The next step (iii) includes reintroducing or returning the body fluid obtained in step (ii) to the target. As described above, the affinity depletion procedure includes contacting the target body fluid with an effective amount of conjugate, multiple conjugates, or a composition thereof contained within the extracorporeal device or within a device or battery connected to the extracorporeal device. Each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the mth carbonyl group, [ka] In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0357] In some embodiments, the conjugate, multiple conjugates or compositions, devices, batteries and apparatus used by the therapeutic method of the present invention are any of those disclosed herein.

[0358] In some embodiments, the conjugate used by the therapeutic method of the present disclosure has structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. [ka] In the formula, m is an integer between 5 and 10.

[0359] In some embodiments, the methods, systems, devices, apparatus and conjugates of the present disclosure may be applicable to any disorder associated with elevated blood ammonia levels, chronic or acute liver conditions and / or chronic or acute lung conditions, cognitive impairment, and any other disorder associated with neuronal and / or neurological damage, as well as hyperammonemia and related conditions.

[0360] In some specific embodiments, the liver condition is hepatic encephalopathy and any related conditions. Hepatic encephalopathy is a decline in brain function that results from severe liver disease. In this condition, the liver is unable to properly remove toxins from the affected blood. This leads to an accumulation of toxins in the bloodstream, which can result in brain damage.

[0361] Hepatic encephalopathy can be acute (short-term) or chronic (long-term). In some cases, individuals with hepatic encephalopathy may become unresponsive and fall into a coma.

[0362] Acute hepatic encephalopathy can also be a sign of end-stage liver failure. Chronic hepatic encephalopathy can be permanent or recurrent.

[0363] Furthermore, hepatic encephalopathy is a syndrome commonly observed in patients with cirrhosis. Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction after elimination of brain disease. Hepatic encephalopathy is characterized by personality changes, intellectual disability, and a decreased level of consciousness. A key prerequisite for this syndrome is the diversion of portal blood into the systemic circulation via portosystemic collateral vessels. Hepatic encephalopathy can also be seen in patients without cirrhosis who have either spontaneously occurring or surgically created portosystemic shunts. The development of hepatic encephalopathy is explained to some extent by the effects of neurotoxic substances occurring in the context of cirrhosis and portal hypertension.

[0364] In some embodiments, the methods, systems, devices, apparatus, and conjugates of this disclosure may be applicable to any condition, symptom, or disorder associated with hyperammonemia. As used herein, hyperammonemia is a pathological accumulation of ammonia in the blood, which can occur in many different clinical situations. Most commonly in adults, hyperammonemia occurs secondary to hepatic dysfunction. However, it is also known to be associated with other medical conditions, surgery, and drug therapies. Less commonly, hyperammonemia has been described as a rare but consistent complication of solid organ transplantation. Lung transplantation is increasingly recognized as an inherent risk factor for the development of this condition, which can result in serious health risks, including long-term neurological complications and even death. A variety of etiologies are attributable to this condition. A growing number of case studies and investigations suggest that sporadic opportunistic infections by Ureaplasma or Mycoplasma species may drive this metabolic disorder in lung transplant recipients. Regardless of etiology, hyperammonemia presents a serious clinical problem with a high reported mortality rate of up to 75%. Surviving patients often suffer from significant long-term neurological complications, such as cognitive impairment. Therefore, it is understood that the methods, systems, devices, apparatus and conjugates of this disclosure may be applicable to the treatment and prevention of hyperammonemia, particularly after solid organ transplantation. In some embodiments, the methods, systems, devices, apparatus and conjugates disclosed in this disclosure are applicable to patients undergoing lung transplantation.

[0365] Furthermore, while ammonia (NH3) is a normal metabolite in the human body, when it reaches hyperphysiological levels in the systemic circulation, it can cause serious neurological damage and potentially lead to death.

[0366] In children, it is classically associated with congenital metabolic disorders relating to urea cycle enzymes and transporters, and is collectively referred to as urea cycle disorder (UCD). Therefore, it is understood that in some embodiments, the methods, systems, devices, apparatus and conjugates of this disclosure may be applicable to treat and / or improve UCD.

[0367] Furthermore, in some embodiments, the methods, systems, devices, apparatus, and conjugates of this disclosure may be applicable to chronic kidney disease, hemorrhagic shock, and any hyperammonemia-related disorders that are well understood and reported in the literature.

[0368] Furthermore, it should be understood that in all cases of hyperammonemia, regardless of the etiology, the mechanism of ammonia's effect on the central nervous system is the same. Once in the systemic circulation, NH3 can cross the blood-brain barrier through multiple mechanisms, including gaseous diffusion, passive diffusion in its soluble form via membrane channels, and competitive diffusion via potassium channels. In the brain, NH3 is taken up by astrocytes and converted to glutamine by glutamine synthetase (GS). This leads to a series of adverse events. Significantly elevated Gln increases osmotic pressure, causing aquaporin disruption, ultimately leading to cerebral edema and hypertension characteristic of hyperammonemia. Simultaneously, astrocytes release various pro-inflammatory cytokines, such as tissue necrosis factor alpha (TNF-α). Astrocyte damage and subsequent downregulation of their glutamate receptors can induce excessive glutamatergic activity at adjacent synapses, leading to excitotoxicity that causes encephalopathy and seizures commonly seen in hyperammonemia.

[0369] Similar physiological changes in increased GABAergic tones occur in Purkinje cells of the cerebellum, which are thought to be responsible for the ataxia and myoclonus also seen with this metabolic disorder. Delays in recognition and appropriate management can lead to significant long-term morbidity, including refractory status epilepticus, motor and cognitive impairment, cerebral palsy, and death. Accordingly, in some embodiments, the methods, systems, devices, apparatus, and conjugates of this disclosure are applicable to any of the disclosed neurological disorders and any associated symptoms. In adults, for example, such a condition may further be characterized by altered mental state, lethargy, mood and personality disturbances, ataxia, vomiting, seizures, loss of consciousness, and potentially death.

[0370] As described above, the subject matter of this disclosure provides methods for treating disorders and any associated conditions with high concentrations of ammonia. Where used herein, “disease,” “disorder,” “condition,” etc., are interchangeable when relating to the health of the subject matter and each and all of such terms have meaning.

[0371] The terms “associated” and “related,” used interchangeably in this specification, mean, when referring to a pathological condition, a disease, disorder, condition, or any pathological condition that shares a common cause, coexists more frequently than simultaneously, or causes at least one of the following: a second disease, disorder, condition, or pathological condition.

[0372] As described above, the subject matter of this disclosure provides methods for treating the disorders specified above. The term “treatment” as used herein means administering a therapeutic dose of the composition of the subject matter of this disclosure that is effective for improving unwanted symptoms associated with the disease, preventing the onset of such symptoms before they occur, delaying the progression of the disease, delaying the worsening of symptoms, enhancing the onset of remission, delaying irreversible damage caused in the progressive chronic stage of the disease, delaying the onset of the progressive stage, reducing the severity of the disease or curing it, improving survival or faster recovery, or preventing the onset of the disease, or a combination of two or more of the above. Treatment may be performed when the hemostatic state first develops, or may be a continuous administration, for example, more than once a day, every 1 to 7 days, every 7 to 15 days, every 15 to 30 days, every 1 to 2 months, every 2 to 6 months, or more, to achieve the therapeutic effects described above.

[0373] The term “prevention” refers to the prevention or reduction of the risk of occurrence or recurrence of a biological or medical event, specifically, a disorder associated with high concentrations of ammonia, which is sought to be prevented in a tissue, system, animal, or human by researchers, veterinarians, physicians, or other clinicians, and the term “preventive effective dose” is intended to mean the amount of the pharmaceutical composition that achieves this objective. Accordingly, in certain embodiments, the method of the subject matter of this disclosure is particularly effective for prevention, i.e., the prevention of disorders and conditions associated with high levels of ammonia. Accordingly, subjects administered with the composition are less likely to experience elevated levels of ammonia and associated symptoms of said disorder, and less likely to experience recurrence in subjects who have already experienced them in the past.

[0374] The term “improvement” as used herein refers to a reduction in symptoms and an improvement in the condition of a subject brought about by the compositions and methods relating to the subject matter of this disclosure, and such improvement may manifest as an increase in the level of ammonia disorder and associated disorders and associated pathological processes described herein, a significant reduction in their magnitude, or an improvement in the physiological condition of the affected subject.

[0375] The term "inhibit" and all variations thereof are intended to include limiting or prohibiting the progression and exacerbation of pathological symptoms or processes, and are related to the symptoms or processes of such pathological processes.

[0376] The term “eliminate” optionally refers to the substantial eradication or removal of pathological symptoms and possibly pathological etiologies by the methods described below in the subject matter of this disclosure.

[0377] The terms “delay,” “delay onset,” and “retard,” and all variations thereof, are intended to encompass the delay of the progression and / or exacerbation of disorders associated with elevated ammonia concentrations, and the symptoms thereof that delay their progression, further exacerbation, or onset so that they appear later than in the absence of treatment in accordance with the subject matter of this disclosure.

[0378] As described above, treatment or prevention includes preventing or delaying the onset of the disease, preventing or delaying the onset of symptoms, and / or reducing the severity of such symptoms that have developed or are expected to develop. These further include improving existing symptoms, preventing further symptoms, and improving or preventing the underlying metabolic causes of the symptoms. The terms “inhibition,” “mitigation,” “reduction,” or “attenuation” as used herein should be understood to refer to any delay, suppression, or reduction of any one of the following percentages of a process, particularly high-level ammonia disturbances and associated disturbances: approximately 1% to 99.9%, particularly approximately 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 99%, or approximately 99% to 99.9%.

[0379] Single or multiple doses on a daily, weekly, or monthly schedule may be administered at dose levels and patterns selected by the treating physician. More specific embodiments typically involve the use of doses two to three times per week.

[0380] The subject matter of this disclosure relates to the treatment of subjects or patients for which such treatment is desired. “Patient” or “subject for which treatment is desired” means any organism that may be infected with the above pathogens and for which the preventive and protective products, kits and methods described herein are desired, including humans, livestock and non-livestock mammals, e.g., dogs and cats, cattle, monkeys, horses and mice, rodents, domesticated birds, aquaculture, fish and exotic ornamental fish. It should be understood that subjects for treatment may also be any reptile or zoo animal.

[0381] "Mammalian subjects" means any mammal, including humans, horses, dogs, and cats, and most specifically humans, for which the proposed treatment is desired. In particular, for non-human subjects, it should be noted that the methods of the subject matter of this disclosure may be carried out by injection (intravenous (IV), intra-arterial (IA), intramuscular (IM), or subcutaneous (SC)), administration by drinking water, feed, spray, oral lavage, and direct administration into the gastrointestinal tract of subjects requiring it.

[0382] The methods discussed herein refer to the use of an effective amount. The terms “effective amount” or “sufficient amount” as used in the methods of the present invention should be understood to mean the amount necessary to achieve the selected result. More specifically, the amount of a particular conjugate disclosed herein is sufficient to deplete and / or remove and / or reduce the concentration of at least one amine from a body fluid, specifically, to deplete or at least reduce ammonia from a body fluid. Furthermore, such an effective amount is sufficient to provide a body fluid containing normal and / or non-toxic levels of ammonia. The “effective treatment amount” as used herein is determined by the severity of the disease, in conjunction with the purpose of prevention or treatment, the route of administration, and the patient’s overall condition (age, sex, weight, and other considerations known to the attending physician). In the context of the present invention, it refers to an effective amount of the conjugate of the present invention used by the devices, systems, apparatus and methods disclosed herein, required to deplete and / or remove and / or reduce the concentration of ammonia in a body fluid in order to treat, prevent, avoid and improve any condition associated with elevated ammonia concentration, as discussed above.

[0383] All scientific and technical terms used herein have their meanings as commonly used in the art unless otherwise specified. The definitions provided herein are for the purpose of facilitating the understanding of certain terms that are frequently used herein and are not intended to limit the scope of this disclosure.

[0384] All definitions defined and used herein should be understood to govern dictionary definitions, definitions in literature incorporated by reference, and / or the ordinary meaning of the defined terms.

[0385] As used herein, the term “approximately” indicates a value that may be a deviation of up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20%, higher or lower than the value mentioned, and the deviation range, including integer values ​​and, where applicable, non-integer values, constitutes a continuous range. As used herein, the term “approximately” means ±10%.

[0386] The indefinite articles “a” and “an” as used herein and in the claims should be understood to mean “at least one” unless explicitly stated otherwise. It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple objects unless otherwise clearly indicated otherwise.

[0387] As used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements thus combined, i.e., elements that are sometimes conjunctive and sometimes disjunctive. Any multiple elements listed in “and / or” should similarly be interpreted as “one or more” of the elements thus combined. Other elements besides those specifically identified by the “and / or” clause may exist, optionally, whether related to or unrelated to those specifically identified elements. Therefore, as a non-restrictive example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising,” could refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), and so on.

[0388] Where used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as inclusive, that is, including at least one of multiple elements or lists of elements, but also including two or more, and optionally including additional unlisted items. Only terms that are explicitly indicated to the contrary, such as “one of ~” or “exactly one of ~” or, where used in the claims, “consisting of ~,” refer to including exactly one element of multiple elements or lists of elements. In general, where used herein, the terms “or” “either,” “one of ~,” “one of ~,” or “essentially consisting of ~” shall be interpreted only as indicating an exclusive choice (i.e., “one or the other, but not both”) when preceded by a term of exclusivity, and where used in the claims, shall have the usual meaning as used in the field of patent law.

[0389] As used herein and in the claims, the phrase “at least one” with respect to a list of one or more elements means at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically enumerated in the list of elements, nor excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to those specifically identified elements or not. Therefore, as a non-restrictive example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") may refer to, in one embodiment, at least one optionally comprising two or more A's and no B (optionally comprising elements other than B); in another embodiment, at least one optionally comprising two or more B's and no A (optionally comprising elements other than A); and in yet another embodiment, at least one optionally comprising two or more A's and at least one optionally comprising two or more B's (and optionally comprising other elements).

[0390] Furthermore, unless explicitly stated otherwise, in any method claimed herein that includes two or more steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are enumerated.

[0391] Throughout this specification and the following examples and claims, unless otherwise required by context, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to be open-ended, meaning “including but not limited to.” As described in the United States Patent Office Manual of Patent Examining Procedures, only the transitional phrases “consisting of” and “consisting essentially of” are closed or semi-closed transitional phrases, respectively. More specifically, the terms “comprises,” “comprising,” “includes,” “including,” and “having,” and their conjugations, mean “including but not limited to.” The term “consisting of” means “including and limited to.” The term "consisting essentially of" means that the composition, method, or structure may include additional components, steps, and / or parts, but only if the additional components, steps, and / or parts do not substantially alter the basic and novel features of the claimed composition, method, or structure.

[0392] It should be noted that various embodiments of the subject matter of this disclosure may be presented in range form. It should be understood that range form is merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the subject matter of this disclosure. Therefore, a range description should be considered to include all possible subranges specifically disclosed and the individual numerical values ​​within those ranges. For example, a range description such as 1–6 should be considered to specifically disclose subranges such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, and the individual numbers within those ranges, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is shown herein, it is understood to include any cited digits (fractions or integers) within the indicated range. The phrases "ranging / ranges between" the first indicated number and the second indicated number, and "ranging / ranges from" the first indicated number to the second indicated number, are used interchangeably herein and mean the first and second indicated numbers, as well as all fractions and integers between them.

[0393] As used herein, the term “method” means a mode, means, technique and procedure for accomplishing a given task (including, but not limited to, modes, means, techniques and procedures that are known to practitioners of the chemical, pharmacological, biological, biochemical and medical fields, or that can be readily developed from known modes, means, techniques and procedures).

[0394] For clarity, it should be understood that certain features of the subject matter described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the subject matter described in the context of a single embodiment may also be provided separately, in any preferred subcombination, or as suitable in any other described embodiment of the subject matter. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments are inoperable without those elements.

[0395] Various embodiments and aspects of the subject matter of this disclosure described above and claimed in the following claims section will be experimentally supported in the following examples.

[0396] As disclosed and described herein, the subject matter of this disclosure is not limited to the specific examples, method steps, and compositions disclosed herein, and such method steps and compositions may vary to some extent. The scope of the subject matter of this disclosure is limited only by the appended claims and their equivalents, and the terms used herein are used solely for the purpose of describing specific embodiments and are not intended to limit them.

[0397] The following embodiments are representative of the techniques used by the inventors in carrying out aspects of the subject matter of this disclosure. While these techniques are illustrative of preferred embodiments for the practice of the subject matter of this disclosure, it should be understood that those skilled in the art will recognize that numerous modifications can be made in light of this disclosure without departing from the spirit and intended scope of the subject matter of this disclosure. [Examples]

[0398] Experimental Procedure Preparation of a linker for coupling to 4% agarose beads Resin active group: -COOH group • Coupled group: -NH2 group • Particle size range of 45-165 μm, average 90 μm • Spherical cross-linked agarose Coupling conditions: 4°C to 25°C, pH: 4.5 to 6 for 1.5 to 24 hours. Coupling can be performed in an organic solvent. • No blocking reaction is required after the coupling reaction. • Store at 2-8℃ protocol: Dissolve the linker to be coupled in the coupling solution (pH: 4.5-6). Preparation of resins for ligand coupling Wash an appropriate amount of resin five times with distilled water (pH 4.5-6). 1. Add the linker solution to the agarose beads in a ratio of 1:0.5 to 1:1 and gently mix to prepare a suspension. 2. Add the carbodiimide solution to the suspension to a final concentration of 0.1 M. 3. Rotate the suspension at 4°C-RT for 4 hours. 4. Adjust the pH of the reaction mixture with 0.1 M NaOH during the first hour of the reaction. 5. Wash the resin with 0.1M acetate buffer (pH 4) containing 0.5M NaCl, and then wash it with 0.1M Tris-HCl buffer (pH 8) containing 0.5M NaCl. 6. Repeat step 5 twice. 7. If no organic solvent was used for coupling, wash the resin with 5-10 times the volume of resin using distilled water. 8. Next, add sulfenic acid according to steps 1-7.

[0399] Measurement of ammonia in plasma To deplete ammonia from plasma, the plasma should be incubated with resin in a 1:10 ratio for 1 hour with shaking, during which ammonia particles collide with and are specifically captured by the resin. The effectiveness of the incubation process was investigated by detecting the ammonia concentration and depletion rate in the control and incubated plasma, i.e., 100 - (incubated plasma concentration / control plasma concentration).

[0400] Ammonia concentration can be detected using an ammonia assay kit (catalog number: KA0810, manufacturer: Abnova). Ammonia or ammonium reacts with an OxiRed probe to produce a product that yields a color (OD 570 nm) that can be easily quantified by a plate reader. The kit can detect 1 nmol (approximately 20 μM) of ammonia or ammonium.

[0401] Establishment of an acute liver failure model in pigs A midline incision was made from the xiphoid process to the pubic bone. The portal vein was incised from the hepatic hilum to the confluence with the splenic vein, avoiding the surrounding tissue and lymph nodes. The inferior vena cava immediately superior to the renal vein was cleansed, clamped with an exclusion clamp, and a 1.5 cm longitudinal incision was made. The portal vein was then clamped and displaced, and end-to-end anastomosis was performed to the inferior vena cava using continuous over-and-over polypropylene 5-0 sutures. The total duration of portal vein occlusion was 11-15 minutes. During this time and for an additional 10 minutes, 1000 ml of 0.9% NaCl was injected into each animal to maintain arterial pressure. Careful incision of structures within the hepatoduodenal ligament was performed to ensure that arterial blood supply to the liver was also completely blocked. At the end of the experiment, the animals were euthanized.

[0402] Example 1 Conjugate synthesis and device assembly A conjugate containing agarose beads, a linker, and sulfuric acid was prepared as described in the experimental procedure. More specifically, 6% agarose beads were bonded to a linker consisting of 15 carbon atoms and sulfonic acid. Figure 15 shows a schematic diagram of the conjugate. The amount of ammonia in the body fluids was calculated based on the standard curve shown in Figure 17.

[0403] Figure 1 shows a non-limiting example of a filter device including the conjugate of the present invention for use in connection with an apheresis mechanism for absorbing ammonia from the blood system. The filter includes a resin having a chemical linker, a housing (plastic), and a general-purpose connecting tube for connecting the filter to the apheresis mechanism.

[0404] Example 2 Depletion of ammonium from pig bodily fluids Preclinical studies were conducted in Phase 1. Animal experiments were performed using pigs (swine). The pigs were housed in an animal room for at least two days prior to the experiment. The conditions in the animal room were controlled (21°C, 30-40% relative humidity, and a 12:12 light-dark cycle). The animals were fed regularly. After two days, all animals were fasted overnight and given free access to water. The animals were monitored by veterinary care services, and their general health status was continuously monitored prior to the experiment. Acute liver failure (ALF), which causes an increase in ammonia concentration, was induced by end-to-end portosystemic shunt, followed by ligation of the hepatic artery, and all animals were given intravenous administration of saline, glucose, and albumin as described in the experimental procedure. Once ALF was initiated, ammonia concentration was monitored. Figure 17A shows an example of the pigs used in this study. The histogram in Figure 17B shows the increase in ammonia concentration over time in the hyper-ammonia model. As shown in the figure, the ammonia concentration dramatically increased to 227 micromoles / liter within 150 minutes.

[0405] In parallel experiments, after ALF induction as described above, animals were connected to a plasma exchange system having the device of the present disclosure, referred to herein as AAPC-300 (AMMONIA ADSORPTION PLASMA COLUMN (AAPC-300), PlasFree ammonia absorber), which includes the conjugate of the present disclosure for filtering ammonia during plasma exchange. At the end of each cycle of hemofiltration, the ammonia concentration was monitored and recorded. Preliminary results showed a significant reduction in ammonia concentration from 227 micromoles / liter to 65 micromoles / liter, thereby establishing the feasibility of the disclosed method for in vivo / ex vivo depletion of the target ammonia.

[0406] Example 3 Depletion of ammonium from human plasma Next, the inventors evaluated the ability of the conjugate and device of the present disclosure to deplete ammonium from a unit of ammonium-enriched human plasma. As shown by the illustrative scheme in Figure 18, a human plasma bag is connected via a flow regulator to the device of the present disclosure containing approximately 270–300 ml of the conjugate disclosed herein (also referred to as AAPC-300). Filtered plasma was collected in the bag as shown in the figure. As presented in Figure 19, measurement of the ammonia concentration in the filtered bag by ELISA showed a significant decrease in ammonia concentration from approximately 120 micromoles per liter to approximately 20 micromoles per liter (a 6-fold reduction).

[0407] Therefore, these results establish the feasibility of using the disclosed methods and devices to prepare commercially available ammonia-free or ammonia-reduced blood products.

Claims

1. It is a device, - A housing comprising at least one fluid inlet port and at least one fluid outlet port, - The housing includes at least one chamber, the at least one chamber defining a reference volume that is in fluid communication with the at least one fluid inlet port and the at least one fluid outlet port, The control volume contains at least one of a conjugate, a plurality of conjugates, or at least one composition comprising the conjugate or plurality of conjugates, wherein the conjugate has a structure of formula I, and the conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 1】 A device characterized in that, in the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A has the ability to scavenge or bind amines.

2. (a) The amine is at least one of methylamine, dimethylamine, or trimethylamine. (b) The linker comprises a linear alkane and m carbonyl groups, (c) The linker comprises a linear alkane and m carbonyl groups, and the linear alkane is saturated or unsaturated. (d) The linker comprises a linear alkane and m carbonyl groups, and the linear alkane is unsaturated. (e) The linear alkane contains 1 to 3 double bonds, and / or (f) The amine is ammonia. The device according to claim 1, which is at least one of the following.

3. (a) The linker has a linear bond between the mth carbonyl group. 【Chemistry 2】 via, or another short alkane chain 【Transformation 3】 Covalently bonded to the scavenger so as to be bonded through, where X is an integer in the range of 1 to 3, (b) The scavenger is a strong acid capable of capturing ammonia. (c) The scavenger is a strong acid capable of capturing ammonia, and the strong acid is sulfuric acid or any derivative thereof, and / or (d) The scavenger is a strong acid capable of capturing ammonia, the strong acid is sulfuric acid or any derivative thereof, and the length (n) of the linear alkane is 15. The device according to claim 1 or 2, wherein the device is at least one of the following.

4. The conjugate comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and acid A covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula II. 【Chemistry 4】 The device according to any one of claims 1 to 3, wherein x is between 0 and 3 in the formula.

5. The conjugate comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. 【Transformation 5】 The device according to any one of claims 1 to 4, wherein x is between 0 and 3 in the formula.

6. The device according to any one of claims 1 to 3, wherein the particles and the linker are covalently bonded, and the bond is a covalent bond via an amino group shown in formula IV. 【Transformation 6】

7. Having structural formula V, the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. 【Transformation 7】 The device according to any one of claims 1 to 5, wherein m is an integer between 5 and 10.

8. (a) The particles are resin beads, (b) The particles are resin beads, and the resin beads contain at least 4% agarose. (c) The particles are resin beads, and the size of the resin beads is in the range of 40 to 170 μm. (d) The device comprises a first barrier member and a second barrier member spaced longitudinally apart from each other across the contrast volume, wherein the first barrier member and the second barrier member are configured to allow unidirectional fluid flow through each barrier member and to block unidirectional fluid flow through each barrier member. (e) The device comprises a first barrier member and a second barrier member, the first barrier member and the second barrier member being installed within the device such as to allow fluid flow through the device from the at least one fluid inlet port to the at least one fluid outlet port, and / or to block fluid flow from the fluid outlet port to the fluid inlet port. (f) The device comprises a first barrier member and a second barrier member, each of the first barrier member and the second barrier member comprising a membrane made from a suitable medically compatible material. The device according to any one of claims 1 to 7, wherein at least one of the above.

9. (a) The housing comprises an outer casing, an inlet end cap, and an outlet end cap, wherein the outer casing has an outer wall extending longitudinally between the inlet end and the outlet end of the outer casing, the inlet end cap is configured to be sealed to the inlet end, and the outlet end cap is configured to be sealed to the outlet end. (b) The housing comprises an outer casing, an inlet end cap, and an outlet end cap, wherein the inlet end cap, the outlet end cap, and the outer casing are each made from a suitable medically compatible material. (c) The housing comprises an outer casing, an inlet end cap, and an outlet end cap, wherein the inlet end cap is configured as a self-locking cap to the outer casing and is configured to allow the inlet end cap to be sealed and locked to the outer casing in a predetermined position, and / or (d) The housing comprises an outer casing, an inlet end cap, and an outlet end cap, and the device comprises a first self-locking device configured to enable the inlet end cap to self-lock with respect to the outer casing. The device according to any one of claims 1 to 8, wherein the device is at least one of the following.

10. (a) The first self-locking device comprises a plurality of first wedge elements and a first flange device, wherein the first wedge elements are provided within the inlet end cap, and the first flange device is provided within the outer casing at a longitudinal distance of a first interval from the inlet end, and the first wedge elements are configured to cooperate with the first flange stop device to provide self-locking of the inlet end cap to the housing, (b) The first self-locking device comprises a plurality of first wedge elements and a first flange device, wherein each of the first wedge elements protrudes longitudinally away from the free end of the inlet end cap. (c) The first self-locking device comprises a plurality of first wedge elements and a first flange device, wherein the first spacing is sufficient to ensure that the free end of each of the inlet end caps abuts against the first flange device when the inlet end cap is fully engaged with the outer casing. (d) The first self-locking device comprises a plurality of first wedge elements and a first flange device, wherein the first flange stop device comprises a plurality of first stop elements corresponding to the plurality of first wedge elements, and each of the first stop elements operates to prevent the inlet end cap from disengaging from the outer casing when each of the first wedge elements is in contact with the outer casing, and / or (e) The first self-locking device comprises a plurality of first wedge elements and a first flange device, the first flange stop device comprising a first flange including a plurality of first notches corresponding to the first wedge elements, each of the first notches having a circumferential length and axial depth sufficient to accommodate the respective first wedge elements therein in the locking configuration. The device according to claim 9, which is at least one of the following.

11. (a) The outlet end cap is configured as a self-locking cap to the outer casing, and is configured to enable the outlet end cap to be sealed and locked to the outer casing in a predetermined position, and / or (b) The device comprises a second self-locking device configured to enable the outlet end cap to self-lock with respect to the outer casing, The device according to claim 9 or 10, which is at least one of the following.

12. (a) The second self-locking device comprises a plurality of second wedge elements and a second flange device, wherein the second wedge elements are provided within the outlet end cap, the second flange device is provided within the outer casing at a longitudinal distance of a second interval from the outlet end, and the second wedge elements are configured to cooperate with the second flange stop device to provide self-locking of the outlet end cap to the housing, and / or (b) The second self-locking device comprises a plurality of second wedge elements and a second flange device as described in (a), wherein each of the second wedge elements protrudes longitudinally away from the free end of the outlet end cap. The device according to claim 11, which is at least one of the following.

13. (a) The second spacing is sufficient to ensure that when the outlet end cap is fully engaged with the outer casing, each of the free ends of the outlet end cap contacts the second flange device. (b) The second flange stop device comprises a plurality of second stop elements corresponding to the plurality of second wedge elements, each of the second stop elements operating to prevent the outlet end cap from disengaging from the outer casing when each of the second wedge elements is in contact with the outer casing. (c) The second flange stopper comprises a second flange including a plurality of second notches corresponding to the second wedge element, each of the second notches having a circumferential length and axial depth sufficient to accommodate each of the second wedge elements in the locking configuration, and / or (d) The control volume is approximately 250 ml to approximately 350 ml. The device according to claim 12, wherein at least one of the following.

14. A device according to any one of claims 1 to 13 for use in depleting at least one amine from at least one liquid substance.

15. The conjugate has a structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. 【Transformation 8】 The device according to any one of claims 1 to 14, wherein m is an integer between 5 and 10.

16. It is a system, - At least one device according to any one of claims 1 to 15, - Apheresis machines and, - Blood mixture reservoir, - A system comprising a conduit system.

17. The system according to claim 16, wherein the conduit system comprises a first conduit configured to provide selective fluid communication between the apheresis machine and the body of a person requiring it, thereby enabling blood to flow from the body of the person requiring it to the apheresis machine.

18. (a) The conduit system comprises a second conduit configured to provide fluid communication from the plasma outlet of the apheresis machine and the at least one device, thereby allowing plasma separated from the blood by the apheresis machine to flow into the at least one device. (b) The conduit system comprises a third conduit configured to provide fluid communication from the at least one device to the blood mixture reservoir, thereby allowing treated plasma treated by the at least one device to flow into the blood mixture reservoir. (c) The conduit system comprises a fourth conduit configured to provide fluid communication from the blood product outlet of the apheresis machine to the blood mixture reservoir, thereby allowing other blood products separated from the blood by the apheresis machine to flow into the blood mixture reservoir. (d) The conduit system comprises a fifth conduit configured to provide selective fluid communication between the blood mixture reservoir and the body of the person requiring it, thereby enabling treated blood to flow from the blood mixture reservoir to the body of the person requiring it. (e) The system comprises a plurality of the devices interconnected in series with respect to each other. (f) The system comprises a plurality of the devices interconnected in parallel with each other via inlet manifolds coupled to each fluid inlet port and outlet manifolds coupled to each fluid outlet port, and / or (g) The system comprises a first plurality of the devices, the groups interconnected in parallel with respect to each other via inlet manifolds coupled to each fluid inlet port and via outlet manifolds coupled to each fluid outlet port, and each of the groups comprises a second plurality of the devices interconnected in series with respect to each other within each of the groups. The system according to claim 16 or 17, wherein at least one of the above.

19. A battery comprising a plurality of devices for use in depleting ammonia from the body fluids of a mammal, wherein the plurality of devices are the devices described in any one of claims 1 to 15.

20. An external device comprising at least one conjugate, or at least one device containing the conjugate, or connected to the at least one device or the battery of the device, wherein the conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 9】 An external device characterized in that, in the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A has the ability to scavenge or bind amines.

21. (a) The device is the device described in any one of claims 1 to 15, and the battery is the battery described in claim 19, and / or (b) The external device is intended for use in depleting ammonia from the body fluids of mammals. The extracorporeal device according to claim 20, which is at least one of the above.

22. A conjugate having structural formula I, wherein the conjugate comprises particles bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 10】 A conjugate characterized in that, in the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A has the ability to scavenge or bind amines.

23. The conjugate according to claim 22, wherein the linker comprises a linear alkane and m carbonyl groups.

24. The conjugate according to claim 23, wherein the linear alkane is saturated or unsaturated.

25. The conjugate according to claim 24, wherein the linear alkane is unsaturated.

26. The conjugate according to claim 25, wherein the linear alkane contains 1 to 3 double bonds.

27. ​​(a) The amine is at least one of methylamine, dimethylamine, or trimethylamine, (b) The amine is ammonia, and / or (c) The linker has a linear bond between the mth carbonyl group. 【Chemistry 11】 via, or another short alkane chain 【Chemistry 12】 Covalently bonded to the scavenger so as to be bonded through, where X is an integer in the range of 1 to 3, A conjugate according to any one of claims 22 to 26, wherein at least one of the above.

28. The conjugate according to claim 22 or 23, wherein the scavenging agent is a strong acid capable of capturing ammonia.

29. The conjugate according to claim 28, wherein the strong acid is sulfuric acid or any derivative thereof.

30. The conjugate according to claim 29, wherein the length (n) of the linear alkane is 15.

31. The conjugate comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and acid A covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula II. 【Chemistry 13】 The conjugate according to any one of claims 22 to 30, wherein x is between 0 and 3 in the formula.

32. The conjugate comprises particles bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (m), and a sulfonic acid covalently bonded to the m-th carbonyl group, wherein the conjugate has structural formula III. 【Chemistry 14】 The conjugate according to any one of claims 22 to 31, wherein x is between 0 and 3 in the formula.

33. The conjugate according to any one of claims 22 to 29, wherein the particles and the linker are covalently bonded, and the bond is a covalent bond via an amino group shown in formula IV. 【Chemistry 15】

34. Having structural formula V, the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. 【Chemistry 16】 The conjugate according to any one of claims 22 to 32, wherein m is an integer between 5 and 10.

35. The conjugate according to any one of claims 22 to 34, wherein the particles are resin beads.

36. (a) The resin beads contain at least 4% agarose, and / or (b) The size of the resin beads is in the range of 40 to 170 μm. A conjugate according to any one of claims 22 to 35, which is at least one of the following.

37. A plurality of conjugates or any composition comprising the plurality of conjugates, each conjugate comprising a particle, at least one linker and at least one scavenger A, or any derivative or analog thereof, wherein the conjugate comprises a particle bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 17】 A plurality of conjugates or any composition comprising the plurality of conjugates, wherein n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and scavenger A has the ability to scavenge or bind amines.

38. The plurality of conjugates according to claim 37, wherein the conjugate is as defined in any one of claims 22 to 36.

39. A plurality of conjugates according to claim 37 or 38 for use in depleting at least one amine from at least one liquid substance.

40. The plurality of conjugates according to claim 39, wherein the amine is ammonia.

41. The plurality of conjugates according to claim 40, wherein the liquid substance is a mammalian bodily fluid, and the plurality of conjugates are for use in depleting ammonia from the mammalian bodily fluid.

42. An effective amount of conjugate, multiple conjugates, or a composition thereof for use in a method for depleting at least one amine from a liquid substance, wherein the method is (i) The step of subjecting the liquid substance to an affinity depletion procedure specific to the at least one amine, (ii) a step of recovering the liquid from which the at least one amine obtained in step (i) has been depleted, The affinity depletion procedure includes contacting the liquid substance with an effective amount of at least one conjugate, a plurality of conjugates, or a composition containing the conjugate or the plurality of conjugates, or applying the liquid substance to a device, battery, or external device containing the conjugate, wherein each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, [Chemistry 18] An effective amount of conjugate, a plurality of conjugates, or a composition thereof, characterized in that, in the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A has the ability to scavenge or bind the amine.

43. An effective amount of conjugate, a plurality of conjugates, or a composition thereof for use according to claim 42, wherein the liquid substance is a mammalian body fluid or any product thereof.

44. (a) The at least one amine is ammonia, and the method is intended for use in depleting ammonia from the body fluids of a mammal, and / or (b) The conjugate is as defined in any one of claims 22 to 36, the plurality of conjugates or compositions are as defined in any one of claims 37 to 41, the device is as defined in any one of claims 1 to 15, the system is as defined in any one of claims 16 to 18, the battery is as defined in claim 19, and the apparatus is as defined in claim 20 or 21. An effective amount of conjugate, a plurality of conjugates, or a composition thereof for use according to claim 42 or 43, which is at least one of the following.

45. An effective amount of conjugate, a plurality of conjugates, or a composition thereof, contained in an external device or a device or battery connected to the external device, used in a method for depleting at least one amine from a body fluid of a subject requiring such depletion by an in vitro procedure, wherein the method (i) A step of transferring the target body fluid to the extracorporeal device, (ii) A step of subjecting the body fluid to an affinity depletion procedure specific to at least one amine, wherein the depletion is performed before, during, or after the blood is transferred in or out of the extracorporeal device, thereby obtaining the extracorporeal body fluid of the subject from which at least one amine has been depleted. (iii) a step of reintroducing or returning the bodily fluid obtained in step (ii) to the subject, The affinity depletion procedure comprises contacting the body fluid with an effective amount of conjugate, a plurality of conjugates, or a composition thereof contained within the external device or within a device or battery connected to the external device, wherein each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 19】 In the formula, n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A is characterized by having the ability to scavenge or bind amines. An effective amount of conjugate, a plurality of conjugates, or a composition thereof, contained within an external device or a device or battery connected to the external device, used in the method described above.

46. An effective amount of conjugate, a plurality of conjugates, or a composition thereof, contained in an external device or a device or battery connected to the external device, for use according to claim 45, (a) The conjugate is as defined in any one of claims 22 to 36, the plurality of conjugates or compositions are as defined in any one of claims 37 to 41, the device is as defined in any one of claims 1 to 15, the system is as defined in any one of claims 16 to 18, the battery is as defined in claim 19, the external device is as defined in claim 20 or 21, and / or (b) The conjugate has structural formula V and comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group, 【Chemistry 20】 In the formula, m is an integer between 5 and 10. An effective amount of conjugate, a plurality of conjugates, or a composition thereof for use according to claim 45, which is at least one of the following.

47. An effective amount of conjugate, multiple conjugates, or a composition thereof, contained within an external device or a device or battery connected to said external device, used in a method for treating, preventing, mitigating, improving, or inhibiting disorders or related pathologies associated with elevated blood ammonia levels in a subject by depleting ammonia from the body fluids of the subject requiring said external device through an external procedure, wherein said method a. A step of transferring the target body fluid to the extracorporeal device, b. A step of subjecting the body fluid to an ammonia-specific affinity depletion procedure, wherein the depletion is performed before, during, or after the blood is transferred to or from the extracorporeal device, thereby obtaining the extracorporeal body fluid of the target from which ammonia has been depleted. c. The step of reintroducing or returning the bodily fluid obtained in step (b) to the subject, The affinity depletion procedure comprises contacting the body fluid with an effective amount of conjugates, a plurality of conjugates, or a composition thereof contained within the external device or within a device or battery connected to the external device, wherein each conjugate comprises a particle bonded to at least one linker containing a chain of n carbon atoms covalently bonded to m carbonyl groups, and at least one scavenger A covalently bonded to the m-th carbonyl group, 【Chemistry 21】 An effective amount of conjugate, a plurality of conjugates, or a composition thereof, contained in an external device or a device or battery connected to the external device, used in the method described above, wherein n is an integer in the range of 5 to 15, m is an integer in the range of 5 to 10, and the scavenger A has the ability to scavenge or bind ammonia.

48. An effective amount of conjugate, a plurality of conjugates, or a composition thereof, contained in an external device or a device or battery connected to the external device, for use according to claim 47, An effective amount of conjugate, a plurality of conjugates or a composition thereof for use according to claim 47, wherein the conjugate is as defined in any one of claims 22 to 36, the plurality of conjugates or compositions is as defined in any one of claims 37 to 41, the device is as defined in any one of claims 1 to 15, the system is as defined in any one of claims 16 to 18, the battery is as defined in claim 19, and the external device is as defined in claim 20 or 21.

49. The conjugate has a structural formula V, and the conjugate comprises particles covalently bonded to at least one linker containing a chain of 15 carbon atoms covalently bonded to m carbonyl groups, and a sulfonic acid covalently bonded to the m-th carbonyl group. 【Chemistry 22】 The formula wherein m is an integer from 5 to 10, the effective amount of conjugate, a plurality of conjugates, or a composition thereof contained in an external device or a device or battery connected to the external device for use according to claim 47 or 48.

50. An effective amount of conjugate, a plurality of conjugates, or a composition thereof contained in an external device or a device or battery connected to the external device, for use according to any one of claims 47 to 49, wherein the disorder associated with an increase in blood ammonia concentration is a chronic hepatic or pulmonary condition and / or cognitive impairment, and / or hyperammonemia and related conditions.

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