In-vitro devices and matrices for the removal of ammonia from biological fluids, methods and uses thereof

Abstract

The present invention relates to devices comprising conjugates, and their use in depleting at least one amine, in particular ammonia, from a body fluid. The present disclosure also provides systems, apparatuses, conjugates, plurality of conjugates, and methods. More particularly, 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 trapping agent A covalently bonded to the mth carbonyl group, wherein n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to capture or bind an amine. 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 devices comprises a straight-chain alkane and m carbonyl groups.

Description

Technical Field

[0001] This invention relates to the field of plasma exchange. More specifically, the invention provides specific apparatus and matrix for depleting ammonia from a biological fluid, the resulting ammonia-free biological fluid, methods, and uses thereof. Background Technology

[0002] The following is a list of references considered relevant to the background art of the currently disclosed topic:

[0003] [1] Treatment of hepatic encephalopathy by on-line hemodiafiltration: a case series study, Shinju Arata, Katsuaki Tanaka, Kazuhisa Takayama, Yoshihiro Moriwaki, Noriyuki Suzuki, Mitsugi Sugiyama&Kazuo Aoyagi, May 21 th ,2010;

[0004] [2]Extracorporeal Detoxification Using the Molecular AdsorbentRecirculating System for Critically Ill Patients with Liver Failure SteffenR. Mitzner, Jan Stange, Sebastian Klammt, Piotr Peszynski, Reinhardt Schmidt and Gabriele Nöldge-Schomburg Jasn February 2001, 12 (suppl 1) S75-S82;

[0005] [3]Ion-exchange resins in the treatment of anuria bm evans. et alLancet 1953;

[0006] [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.

[0007] [5]Hyperkalemia in chronic kidney disease, Renato Watanabe-Rev.Assoc. Med. Bras. vol.66 supl.1 São Paulo 2020 Epub Jan 13, 2020.

[0008] [6]Effects of potassium adsorption filters on the removal of ammoniafrom blood products Hiroshi Fujita, kYoko Shiotani, et al, March 2018;

[0009] [7]Blood Ammonia Reduction by Potassium Exchange ResinExperimentation in Eck-Fistula Dogs, GEORGE D. ZUIDEMA et al .1963.

[0010] [8]Membrane unit and device for cleansing blood, US4183811A;

[0011] [9]Liver support system, WO2014079681A2;

[0012]

[10] System and method for extracorporeal blood treatment,WO2016205221A1-

[0013]

[11] WO2004014315A2;

[0014]

[12] US3963613A;

[0015]

[13] JP2008093244A;

[0016]

[14] CN100486651C;

[0017]

[15] CN109692372A.

[0018] The acknowledgment of the above references in this document should not be construed as implying that these references are in any way related to the patentability of the currently disclosed subject matter. Summary of the Invention

[0019] In a first aspect of the invention, there is a device comprising:

[0020] - A housing having at least one fluid inlet port and at least one fluid outlet port;

[0021] The housing includes at least one chamber defining a control volume in fluid communication with at least one fluid inlet port and at least one fluid outlet port. In some embodiments, the control volume contains at least one of the following substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates. More specifically, the conjugate comprises particles bonded to at least one linker group, the at least one linker group comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0022]

[0023] Formula I

[0024] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap 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 device disclosed in this invention comprises a straight-chain alkane and m carbonyl groups.

[0026] In some other implementations, the straight-chain alkanes are either saturated or unsaturated.

[0027] Furthermore, in some embodiments, the straight-chain alkanes of the conjugates of the apparatus disclosed in this invention are unsaturated.

[0028] In some implementations, the straight chain contains between one and three double bonds.

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

[0030] In some other embodiments, the linker of the conjugate of the device disclosed in this invention is connected via a straight bond at the m-th carbonyl group.

[0031] ( ) or linked through another short alkane chain ( X is covalently attached to the trap in the manner of X, where X is an integer in the range of 1 to 3.

[0032] In some embodiments, the trapping agent of the conjugate of the device disclosed in this invention is a strong acid capable of capturing ammonia.

[0033] Furthermore, in some implementations, the strong acid is sulfuric acid or any derivative thereof.

[0034] In some other embodiments, the length (n) of the straight-chain alkane is 15.

[0035] In some embodiments, the conjugate of the device disclosed in this invention comprises particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, the conjugate having structural formula II:

[0036]

[0037] Formula II

[0038] Where x is between 0 and 3.

[0039] Furthermore, in some embodiments, the conjugate of the device disclosed in this invention comprises particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, the conjugate having structural formula III:

[0040]

[0041] Formula III

[0042] Where x is between 0 and 3.

[0043] In some embodiments, the particles and the linker are covalently linked, and the bond is a covalent bond realized via an amino group, as presented in Formula IV:

[0044]

[0045] Formula IV

[0046] In some embodiments, the conjugate of the device disclosed in this invention has the structural formula V. More specifically, the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0047]

[0048] Formula V

[0049] Where m is an integer between 5 and 10.

[0050] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads; therefore, in some embodiments, the resin beads are agarose resin, which may contain between about 2% and 10% agarose. Further, in some embodiments, the resin beads may contain between 3% and 9% agarose, and even further, in some embodiments, the resin beads may contain between 4% and 8% agarose. According to any more specific, non-limiting embodiment, the resin beads optionally contain at least 4% agarose.

[0051] In some other embodiments, the size of the resin beads is in the range of 40µm to 170µm.

[0052] In some other embodiments, the device includes a first barrier member and a second barrier member longitudinally spaced apart from each other via the control volume, each of the first and second barrier members being configured to allow fluid to flow through the respective barrier member in one direction and to block fluid from flowing through the respective barrier member in the opposite direction.

[0053] In some embodiments, the first barrier member and the second barrier member are installed in the device in such a way that fluid can flow from at least one fluid inlet port through the device to at least one fluid outlet port while simultaneously blocking fluid from flowing from the fluid outlet port to the fluid inlet port.

[0054] In some other embodiments of the device disclosed in this invention, each of the first barrier member and the second barrier member comprises a membrane made of a suitable material.

[0055] Furthermore, the housing includes an outer shell, an inlet end cap, and an outlet end cap, wherein the outer shell includes an outer wall extending longitudinally between the inlet end and the outlet end of the outer shell. The inlet end cap is configured for sealingly mounting to the inlet end, and the outlet end cap is configured for sealingly mounting to the outlet end.

[0056] In some other embodiments of the device according to this disclosure, the inlet end cap, the outlet end cap, and the housing are each made of a suitable medically compatible material.

[0057] In some embodiments, the inlet end cap is configured as a self-locking cap relative to the housing and is configured to allow the inlet end cap to be locked in place in a sealing manner relative to the housing.

[0058] Furthermore, in some embodiments, the device disclosed in this invention includes a first self-locking arrangement configured to enable the inlet end cap to self-lock relative to the housing.

[0059] In some embodiments, the first self-locking arrangement includes a plurality of first wedge elements and a first flange arrangement. Furthermore, these first wedge elements are disposed in the inlet end cap, and the first flange arrangement is disposed in the housing at a position longitudinally spaced a first distance from the inlet end, and the first wedge elements are configured to engage with the first flange stop arrangement to provide self-locking of the inlet end cap relative to the housing.

[0060] In some other embodiments of the device disclosed in this invention, each first wedge element protrudes longitudinally away from the free end of the first end cap.

[0061] In some implementations, the first spacing is sufficient to ensure, for example, that the corresponding free end of the inlet end cap comes into abutment contact with the first flange arrangement when the inlet end cap is fully engaged with the housing.

[0062] In some embodiments of the device disclosed in this invention, the first flange stop arrangement includes a plurality of first stop elements corresponding to a plurality of first wedge elements. Furthermore, each first stop element, when in abutment with a corresponding first wedge element, serves to prevent the inlet end cap from detaching from the housing.

[0063] In some embodiments of the device disclosed in this invention, the first flange stop arrangement includes a first flange that includes a plurality of first slits corresponding to the first wedge elements. Furthermore, each of the first slits has a circumferential length and axial depth sufficient to allow a corresponding first wedge element to be received therein in a locking configuration.

[0064] In some implementations, the outlet end cap is configured as a self-locking cap relative to the housing and is configured to allow the outlet end cap to be locked in place in a sealing manner relative to the housing.

[0065] In some embodiments, the apparatus of this disclosure includes a second self-locking arrangement configured to enable the outlet end cap to self-lock relative to the housing.

[0066] In a more specific embodiment of the device disclosed in this invention, the second self-locking arrangement includes a plurality of second wedge elements and a second flange arrangement. These second wedge elements are disposed in the outlet end cap, and the second flange arrangement is disposed in the housing at a position longitudinally spaced a second distance from the outlet end. Furthermore, these second wedge elements are configured to cooperate with the second flange stop arrangement to provide self-locking of the outlet end cap relative to the housing.

[0067] In some implementations, each second wedge element protrudes longitudinally away from the free end of the second end cap.

[0068] In some other embodiments of the device disclosed in this invention, the second spacing is sufficient to ensure, for example, that the respective free end of the outlet end cap is in abutment contact with the second flange arrangement when the outlet end cap is fully engaged with the housing.

[0069] In some other embodiments, the second flange stop arrangement includes a plurality of second stop elements corresponding to a plurality of second wedge elements. Furthermore, each second stop element, when in abutment with its corresponding second wedge element, serves to prevent the outlet end cap from detaching from the housing.

[0070] In some embodiments, the second flange stop arrangement includes a second flange that includes a plurality of second slits corresponding to the second wedge elements. Furthermore, each of the second slits has a circumferential length and axial depth sufficient to allow a corresponding second wedge element to be received therein in a locking configuration.

[0071] In some embodiments of the device disclosed in this invention, the control volume is between about 250 ml and about 350 ml. In still other embodiments, the control volume is about 250 ml, 255 ml, 260 ml, 265 ml, 270 ml, 275 ml, 280 ml, 285 ml, 290 ml, 295 ml, 300 ml, 305 ml, 310 ml, 315 ml, 320 ml, 325 ml, 330 ml, 335 ml, 340 ml, 345 ml, or 350 ml. Furthermore, in some embodiments, the control volume is between about 257 ml and about 326 ml.

[0072] In some embodiments, the apparatus of this disclosure is configured to deplete at least one amine from at least one liquid substance.

[0073] In some specific embodiments, the amine depleted by the device disclosed in this invention is ammonia.

[0074] In some other embodiments, the device of the present invention is configured to deplete at least one amine from a liquid substance, which may be a mammalian body fluid. Thus, in some embodiments, the device is used to deplete ammonia from a mammalian body fluid.

[0075] In some specific embodiments, the conjugate of the device disclosed in this invention has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and sulfonic acid covalently bonded to the mth carbonyl group.

[0076]

[0077] Formula V

[0078] Where m is an integer between 5 and 10.

[0079] Another aspect of this disclosure relates to a system comprising:

[0080] - At least one device as defined in this disclosure;

[0081] - Apheresis blood component collection machine;

[0082] - Blood mixing reservoir; and

[0083] - Catheter system.

[0084] In some implementations, the catheter system includes a first catheter configured to provide selective fluid communication between the apheresis component machine and the body of the subject in need, thereby enabling blood to flow from the subject's body to the apheresis component machine.

[0085] In some embodiments, the catheter system includes a second catheter configured to provide fluid communication from the plasma outlet of the apheresis component machine to at least one device, thereby enabling plasma separated from blood by the apheresis component machine to flow into the at least one device.

[0086] Furthermore, in some embodiments, the catheter system includes a third catheter configured to provide fluid communication from at least one device to a blood mixing reservoir, thereby enabling processed plasma processed by the at least one device to flow into the blood mixing reservoir.

[0087] In some embodiments, the catheter system includes a fourth catheter configured to provide fluid communication from the blood product outlet of the apheresis component machine to a blood mixing reservoir, thereby enabling other blood products separated from the blood by the apheresis component machine to flow into the blood mixing reservoir.

[0088] In some other embodiments, the catheter system includes a fifth catheter configured to provide selective fluid communication between the blood mixing reservoir and the body of the subject in need, thereby enabling treated blood to flow from the blood mixing reservoir to the body of the subject in need.

[0089] It should be noted that in some embodiments of the system disclosed in this invention, the desired subject is a subject suffering from at least one condition associated with elevated blood ammonia levels. Specifically, any of these conditions will be discussed in conjunction with other aspects of this invention.

[0090] In some embodiments, the system disclosed in this invention includes a plurality of devices disclosed herein that are interconnected in series with each other.

[0091] In some other embodiments, the system disclosed in this invention includes a plurality of said devices interconnected in parallel with each other via an inlet manifold connected to each respective fluid inlet port and an outlet manifold connected to each respective fluid outlet port.

[0092] In some other embodiments, the system disclosed in this invention includes a first plurality of devices interconnected in parallel with each other via inlet manifolds connected to each respective fluid inlet port and via outlet manifolds connected to each respective fluid outlet port, and wherein each of these groups includes a corresponding second plurality of devices interconnected in series with each other within the respective group.

[0093] Another aspect of this disclosure relates to a battery for depleting ammonia from the bodily fluids of a mammal, comprising a plurality of devices as defined in this disclosure.

[0094] Another aspect provided in this disclosure relates to a battery for depleting ammonia from the bodily fluids of a mammal, comprising a plurality of devices as defined in this disclosure.

[0095] Another aspect of this disclosure relates to an in vitro device comprising at least one conjugate, or at least one device comprising the conjugate, or connected to at least one device or a series of devices. More specifically, the conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0096]

[0097] Formula I

[0098] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. Further, the device includes:

[0099] - A housing having at least one fluid inlet port and at least one fluid outlet port;

[0100] - The housing includes at least one chamber defining a control volume in fluid communication with at least one fluid inlet port and at least one fluid outlet port;

[0101] The controlled volume contains at least one of the following substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates.

[0102] Another aspect relates to an in vitro device comprising at least one conjugate, or at least one device comprising the conjugate. In some embodiments, the in vitro device may be connected to at least one such device or a series of such devices. In a more specific embodiment, the conjugate of the in vitro device disclosed herein may comprise particles bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0103]

[0104] Formula I

[0105] Wherein, 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 trapping agent A is characterized by having the ability to trap or bind amines, optionally, the amine being at least one of methylamine, dimethylamine, or trimethylamine. In some further embodiments, the device included in or connected to an external device may include:

[0106] - A housing having at least one fluid inlet port and at least one fluid outlet port;

[0107] The housing includes at least one chamber defining a control volume 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 substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates.

[0108] In some embodiments of the in vitro device of this disclosure, the device and the battery are as defined in this disclosure. In some embodiments, the conjugate, multiple conjugates or compositions, the device for the in vitro device, and the battery are as defined in this disclosure.

[0109] In some embodiments, the extracorporeal device of this disclosure is suitable for depleting ammonia from the bodily fluids of mammals.

[0110] Another aspect of this disclosure relates to a conjugate having structural formula I. More specifically, the conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group;

[0111]

[0112] Formula I

[0113] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. Furthermore, in some embodiments, having the ability to trap means binding and / or trapping at least one amine.

[0114] In some embodiments, the linker of the conjugate disclosed in this invention comprises a straight-chain alkane and m carbonyl groups.

[0115] Furthermore, in some embodiments, the straight-chain alkane of the conjugates disclosed in this invention is saturated or unsaturated.

[0116] In some implementations, the straight-chain alkanes are unsaturated.

[0117] In some other implementations, the straight chain contains between one and three double bonds.

[0118] Furthermore, in some embodiments, the trapping agent A of the conjugate disclosed herein has the ability to capture and / or bind at least one amine, specifically, ammonia.

[0119] In some further embodiments of the conjugates disclosed in this invention, the linker is connected via a straight bond at the m-th carbonyl group ( ) or linked through another short alkane chain ( X is covalently attached to the trap in the manner of X, where X is an integer in the range of 1 to 3.

[0120] Furthermore, in some embodiments, the trapping agent of the conjugate disclosed in this invention is a strong acid capable of capturing ammonia.

[0121] In some other embodiments, the strong acid is sulfuric acid or any derivative thereof.

[0122] In some implementations, the length (n) of the straight-chain alkane is 15.

[0123] Furthermore, in some embodiments, the conjugate of this disclosure comprises particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, the conjugate having structural formula II:

[0124]

[0125] Formula II

[0126] Where x is between 0 and 3.

[0127] In some other embodiments, the conjugate of this disclosure comprises particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, the conjugate having structural formula III:

[0128]

[0129] Formula III

[0130] Where x is between 0 and 3.

[0131] In some embodiments of the conjugates disclosed herein, the particles and the linker are covalently linked, and the bond is a covalent bond realized via an amino group, as presented in Formula IV:

[0132]

[0133] Formula IV.

[0134] Furthermore, in some embodiments, the conjugate disclosed herein has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0135]

[0136] Formula V

[0137] Where m is an integer between 5 and 10.

[0138] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads; therefore, in some embodiments, the resin beads are agarose resin, which may contain between about 2% and 10% agarose. Further, in some embodiments, the resin beads may contain between 3% and 9% agarose, and even further, in some embodiments, the resin beads may contain between 4% and 8% agarose. In some other embodiments, the particles of the conjugate disclosed in this invention are resin beads. Further, the resin beads optionally contain at least 4% agarose.

[0139] In some embodiments of the conjugates disclosed in this invention, the size of the resin beads is in the range of 40µm to 170µm.

[0140] Another aspect of this disclosure relates to a plurality of conjugates, or any composition comprising said plurality of conjugates. Each conjugate comprises particles, at least one linker, and at least one trapping agent A, or any derivative or analog thereof, the conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group;

[0141]

[0142] Formula I

[0143] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0144] In some embodiments, the conjugate in the plurality of conjugates is any one of the conjugates disclosed herein.

[0145] In some embodiments, the various conjugates disclosed herein are used to deplete at least one amine from at least one liquid substance.

[0146] In some embodiments of the various conjugates disclosed in this invention, the amine is ammonia.

[0147] In some implementations, the liquid substance is the body fluid of a mammal.

[0148] Furthermore, in some other embodiments, multiple conjugates are used to deplete ammonia from the body fluids of mammals.

[0149] Another aspect of this disclosure relates to a method for depleting at least one amine from a liquid substance. More specifically, the method includes the following steps:

[0150] In the first step (i), the liquid substance is subjected to an affinity depletion process specifically for the at least one amine. The next step (ii) involves recovering the at least one amine-depleted liquid obtained in step (i). In some embodiments, the affinity depletion process includes contacting the liquid substance with an effective amount of at least one conjugate, multiple conjugates, or a composition containing the conjugate or multiple conjugates, or applying the liquid substance to a device, battery, or external device containing a conjugate of the present disclosure. In a more specific embodiment, each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0151]

[0152] Formula I

[0153] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0154] In some embodiments, the liquid substance used in the methods disclosed herein is mammalian body fluid or any product thereof.

[0155] In some other 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. Therefore, in some embodiments, the method of this disclosure is used to deplete ammonia from the body fluids of mammals.

[0156] It should be noted that in some embodiments, any of the conjugates, multiple conjugates or compositions, devices and / or batteries and / or equipment used by the methods discussed herein are as defined in this invention.

[0157] Another aspect of the invention relates to a method for depleting at least one amine from the bodily fluids of a subject in need. More specifically, the method may include contacting the bodily fluids with an effective amount of the conjugate, multiple conjugates, or a combination thereof, or within a device or battery containing the conjugate, or alternatively, with an in vitro device containing the conjugate or device described herein or connected to the conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0158]

[0159] Formula I

[0160] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step involves recovering the amine-free bodily fluid and, optionally, reintroducing the bodily fluid into the subject in need.

[0161] In some other specific and non-limiting embodiments, the method may include the use of an external procedure. More specifically, the method may include the following steps:

[0162] First, in step (i), the subject's bodily fluids are transferred to an external device.

[0163] The next step (ii) involves subjecting the body fluid to an affinity depletion procedure dedicated to at least one amine, wherein the depletion is performed before, during, or after the transfer of blood into and from the device, thereby obtaining the subject's in vitro body fluid depleted of at least one amine.

[0164] The next step (iii) involves reintroducing or returning the bodily fluids obtained in step (ii) to the subject. As noted above, the affinity depletion procedure involves contacting the subject's bodily fluids with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or within a device or battery connected to the external device. Each conjugate comprises particles bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0165]

[0166] Formula I

[0167] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0168] In some embodiments, the conjugates, multiple conjugates or compositions, devices, batteries and equipment used in the methods of the present invention are any of those disclosed in this disclosure.

[0169] In some embodiments, the conjugate used in the method of this disclosure has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0170]

[0171] Formula V

[0172] Where m is an integer between 5 and 10.

[0173] Another aspect of this disclosure relates to a method for treating, preventing, ameliorating, or inhibiting conditions or pathological conditions associated with elevated blood ammonia levels in a subject by depleting ammonia from the body fluids of the subject in need.

[0174] More specifically, the treatment methods disclosed herein may include contacting the bodily fluids of a treated subject with an effective amount of the conjugate, multiple conjugates, or a combination thereof, or within a device or battery containing the conjugate, or alternatively, with an external device containing the conjugate or device described herein or connected to the conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0175]

[0176] Formula I

[0177] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step involves recovering the amine-free bodily fluid and optionally reintroducing the bodily fluid into the treated subject.

[0178] In some other specific and non-limiting embodiments, these methods may include the use of an external procedure. More specifically, the method may include the following steps:

[0179] First, in step (i), the subject's bodily fluids are transferred to an external device.

[0180] The next step (ii) involves subjecting the body fluid to an affinity depletion procedure dedicated to at least one amine, wherein the depletion is performed before, during, or after the transfer of blood into and from the device, thereby obtaining an in vitro body fluid of the treated subject depleted of at least one amine.

[0181] The next step (iii) involves reintroducing or returning the bodily fluid obtained in step (ii) to the subject. As noted above, the affinity depletion procedure involves contacting the subject's bodily fluid with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or within a device or battery connected to the external device. Each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0182]

[0183] Formula I

[0184] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0185] In some embodiments, the conjugates, multiple conjugates or compositions, devices, batteries and apparatus used in the treatment methods of the present invention are any of those disclosed in this disclosure.

[0186] In some embodiments, the conjugate used in the treatment methods of this disclosure has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0187]

[0188] Formula V

[0189] Where m is an integer between 5 and 10.

[0190] In some implementations, the methods disclosed herein can treat any condition associated with elevated blood ammonia levels, including chronic liver or lung conditions and / or cognitive decline, and / or hyperammonemia and related conditions.

[0191] In some specific implementations, liver condition refers to hepatic encephalopathy and any related conditions.

[0192] These and other aspects of the invention will become apparent from the following disclosure. Attached Figure Description

[0193] To better understand the subject matter disclosed herein and to illustrate how it can be implemented in practice, implementation methods will now be described by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0194] Figure 1 This is an isometric partial fracture view of an apparatus according to one embodiment of the subject matter disclosed in the present invention.

[0195] Figure 2 yes Figure 1 Isometric exploded view of the implementation plan.

[0196] Figures 3(a) to 3(c). Figure 3(a) is... Figure 1 A side view of the outer shell of the embodiment; Figure 3(b) is a front view of the embodiment of Figure 3(a); Figure 3(c) is a cross-sectional side view of the embodiment of Figure 3(b) taken along BB.

[0197] Figures 4(a) to 4(d). Figure 4(a) is... Figure 1 Figure 4(b) is a side view of the inlet end cap of the embodiment shown in Figure 4(a) taken along AA; 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).

[0198] Figures 5(a) to 5(d). Figure 5(a) is... Figure 1 Figure 5(b) is a side view of the outlet end cap of the embodiment; Figure 5(c) is a cross-sectional side view of the embodiment of Figure 5(a) taken along A'-A'; Figure 5(d) is a rear isometric view of the embodiment of Figure 5(a);

[0199] Figure 6 yes Figure 1 Partial isometric exploded view of the first self-locking arrangement of the implementation scheme.

[0200] Figure 7 yes Figure 1 Partial isometric exploded view of the second self-locking arrangement of the implementation scheme.

[0201] Figure 8 yes Figure 1 A cross-sectional side view of the first barrier component assembly of the implementation scheme.

[0202] Figure 9 yes Figure 1 A cross-sectional side view of the second barrier component assembly in the implementation scheme.

[0203] Figure 10 This is a schematic diagram of a system according to an embodiment of the subject matter disclosed in the present invention.

[0204] Figure 11 It is based on Figure 10 A schematic diagram of an alternative variant of the implementation scheme.

[0205] Figure 12 It is based on Figure 10 A schematic diagram of an alternative variant of the implementation scheme.

[0206] Figure 13 It is based on Figure 10 A schematic diagram of an alternative variant of the implementation scheme.

[0207] Figure 14 It is based on Figure 10 A schematic diagram of an alternative variant of the implementation scheme.

[0208] Figure 15 : Conjugates containing sulfonic acid

[0209] This figure illustrates a schematic diagram of the chemical reaction used to prepare a conjugate containing sulfonic acid.

[0210] Figure 16 Ammonia Standard Curve

[0211] A coordinate graph representing the standard curve used to calculate ammonia concentration.

[0212] Figures 17A to 17B Establish a porcine superammonia model

[0213] Figure 17A An example of a pig that has been anesthetized and given a central intravenous infusion of toluidine and ketamine is shown.

[0214] Figure 17B The bar chart shown illustrates ammonia levels monitored every 30 minutes before and after the procedure.

[0215] Figure 18 ammonia depletion process

[0216] This figure illustrates the process of depleting ammonia from a human plasma unit. A plasma bag is connected to the ammonia depletion device of this disclosure. A flow regulator adjusts the plasma flow rate into the device, and a clamp is used to stop the plasma flow rate in case of leakage. The filtered blood products are then collected in the bag.

[0217] Figure 19 The process of ammonia depletion in human blood plasma

[0218] A human plasma bag (rich in ammonia) is connected to the device disclosed herein (specifically designated herein as an AAPC-300 filter) via a Luer lock connection. The plasma is dispensed at an adjusted rate of 150 mL / min (from... Figure 18 The flow rate was regulated by the flow regulator shown. Plasma was collected in 200 mL tubes. Data from the filtered plasma were read using an ELISA reader to assess the ammonia depletion rate. Statistical data were calculated using a Student's t-test (two-tailed distribution with equal variance). Data are expressed as mean ± SD. Detailed Implementation

[0219] This disclosure, in its broadest sense, provides conjugates, multiple conjugates, and compositions comprising the multiple conjugates, each conjugate having the general formula (I').

[0220] XYZ (I')

[0221] in:

[0222] X represents the solid carrier component, such as particles;

[0223] Y is the chemically reactive part that connects the X and Z parts;

[0224] Z is a portion comprising at least one of a trapping agent, its derivatives, or its analogues; and

[0225] Each "-" represents an interaction / association, such as a chemical bond optionally containing one or more intermediary atoms serving as spacer groups or as selective guiding motifs. Therefore, in a first aspect, the present invention provides an apparatus comprising:

[0226] - A housing having at least one fluid inlet port and at least one fluid outlet port;

[0227] - The housing includes at least one chamber defining a control volume in fluid communication with at least one fluid inlet port and at least one fluid outlet port;

[0228] The controlled volume contains at least one of the following substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates. In some specific embodiments, the conjugate of the device disclosed herein has structural formula I, the conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group;

[0229]

[0230] Formula I

[0231] Where 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 trapping agent A is characterized by having the ability to trap or bind amines. As noted above, in some embodiments, the linker group comprises 5 to 15 carbon atoms. In some embodiments, since the length of a carbon atom is about 1.5 angstroms, the length of the linker group can be in the range of less than 7.5 angstroms to more than 22.5 angstroms. In still other embodiments, the linker group further comprises between 5 and 10 carbonyl groups. Since the length of each carbonyl group can be about 1.3 angstroms, its length can be in the range of less than about 6.5 angstroms to more than 13 angstroms.

[0232] In other words, this disclosure provides an apparatus comprising a conjugate, the conjugate comprising three parts:

[0233] -Particles;

[0234] - Connecting base; and

[0235] -Collecting agent.

[0236] These three parts are connected to each other by connecting groups that link the particles and the trapping agent.

[0237] The linker of the present invention typically includes two groups, wherein the first group includes straight-chain alkanes containing n carbon atoms, and the second group includes m covalently bonded carbonyl groups.

[0238] In some embodiments, the linear alkane of the linker of the conjugate of the present disclosure is saturated or unsaturated.

[0239] In some embodiments, the straight-chain alkane group may be saturated, while in other embodiments, the group may be unsaturated.

[0240] In embodiments where the straight-chain alkane group is unsaturated, the chain may contain between one and three double bonds.

[0241] The trapping agent portion designated as A in this document may include any reagent having the ability to "capture" or bind amines.

[0242] In the context of this disclosure, the term "amine" refers to any compound or functional group containing at least one basic nitrogen atom and at least one lone pair of electrons. Amines according to this disclosure may include any primary, secondary, and tertiary amines with a molecular weight (MW) between at least 17 Daltons and at most 70 Daltons.

[0243] In some embodiments, the amine is an alkylamine, dialkylamine, or trialkylamine, wherein the molecular weight (MW) of such amine is between 17 Daltons and 70 Daltons.

[0244] In some other embodiments, the amine is selected from methylamine, dimethylamine, or trimethylamine.

[0245] In one specific implementation, the amine is ammonia.

[0246] The linker of the present invention uses the m-th carbonyl group via a straight bond ( ) or linked through another short alkane chain ( X is covalently attached to the trap in the manner of X, where X is an integer in the range of 1 to 3.

[0247] In some embodiments, the trapping agent can be any ion exchange material. More specifically, since ammonia is a cation at physiological pH, it can bind to cation exchangers. Other alternatives covered by this invention include NHS and epoxy resins.

[0248] In some implementations, the trapping agent is an acid.

[0249] In some implementations, the acid is a strong acid capable of capturing amines.

[0250] In some implementations, the amine is as defined above.

[0251] In some other implementations, the amine is ammonia.

[0252] In the context of the disclosure provided herein, the term “strong acid” is any acid with a pKa value less than 1.

[0253] pKa is sometimes below 0, sometimes below (-1), sometimes below (-2), sometimes below (-3), sometimes below (-4), sometimes below (-5), sometimes below (-6), sometimes below (-7), sometimes below (-8), and sometimes below (-9).

[0254] 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, analogs thereof, and derivatives thereof.

[0255] In one specific implementation, the acid is sulfuric acid or a derivative thereof.

[0256] Sulfonic acid derivatives can be any molecule having the following general formula:

[0257]

[0258] R is an organic alkyl or aryl group.

[0259] In the implementation scheme, the sulfonic acid derivative is selected from taurine, PFOS, p-toluenesulfonic acid, and coenzyme M.

[0260] In some implementations, R is -H.

[0261] In the most general terms, the length of the straight-chain alkane determines the specificity of the conjugate. Too long a linker will capture non-specific / unwanted molecules, such as proteins and amino acids (because they contain amino groups). Short linkers will reduce the conjugate's ability to capture ammonia and ammonium cations.

[0262] Therefore, in the implementation scheme, the length (n) of the straight-chain alkane is between 5 and 20 carbon atoms, specifically, between 5 and 19 carbon atoms, between 5 and 18 carbon atoms, between 5 and 17 carbon atoms, between 5 and 16 carbon atoms, between 5 and 15 carbon atoms, between 5 and 14 carbon atoms, between 5 and 13 carbon atoms, between 5 and 12 carbon atoms, and between 5 and 11 carbon atoms. The lengths (n) of the straight-chain alkane are: between 5 and 10 carbon atoms, between 6 and 20 carbon atoms, between 7 and 20 carbon atoms, between 8 and 20 carbon atoms, between 9 and 20 carbon atoms, between 10 and 20 carbon atoms, between 1 and 20 carbon atoms, between 12 and 20 carbon atoms, between 13 and 20 carbon atoms, between 14 and 20 carbon atoms, and between 15 and 20 carbon atoms. In some other embodiments, the length (n) of the straight-chain alkane is sometimes between 10 and 15 carbon atoms, sometimes between 12 and 15 carbon atoms, sometimes between 13 and 15 carbon atoms, and sometimes between 14 and 15 carbon atoms. In some specific embodiments, the length (n) of the straight-chain alkane is 5 or less, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or longer. In one specific and non-limiting embodiment, n is 15.

[0263] Without being bound by theories or mechanisms, the carbonyl moiety provides adequate bulkiness, preventing amino acids and peptides from attaching to the acidic portion of the conjugate. The inventors of this disclosure unexpectedly discovered that between five and ten carbonyl groups bonded together provide sufficient bulkiness to prevent larger molecules from being trapped by the acidic portion of the conjugate.

[0264] In other embodiments of the invention, an apparatus is provided in which the conjugate of the apparatus disclosed herein comprises particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, the conjugate having structural formula II:

[0265]

[0266] Formula II

[0267] Where x is between 0 and 3.

[0268] When x is 0, the m-th carbonyl group is directly attached to the acid.

[0269] In some other embodiments, the present invention provides an apparatus comprising a conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, the conjugate having structural formula III:

[0270]

[0271] Formula III

[0272] Where x is between 0 and 3.

[0273] In some implementations, x is between 0 and 2, and sometimes between 0 and 1. Sometimes x is 1, and sometimes x is 0.

[0274] When x is 0, the m-th carbonyl group is directly attached to the acid.

[0275] In some embodiments, the conjugate of the present disclosure is configured to act as an amine trap, thereby exhibiting a neutralization reaction of the amine. In a more specific embodiment, the amine is ammonium.

[0276] Furthermore, in some embodiments, the linker portion of the conjugate disclosed herein is linked to the particle via any suitable functional group that allows the particle to be linked to a straight-chain alkane.

[0277] Unbound by theory or reaction mechanism, the conjugates of the present invention act as amine traps, which exhibit a neutralization reaction of an amine with each acid trap as defined above:

[0278]

[0279] Where -H is the free hydrogen atom of the acid, and (:) is the free electron of the amine.

[0280] In embodiments where the acid is a sulfonic acid and the amine is ammonia, the proton (H) + The following is an example of donating two free electrons to ammonia:

[0281]

[0282] This results in the formation of ionic bonds between the conjugate acid and the conjugate base.

[0283] The linker portion disclosed herein can be linked to particles via any group known in the art, which allows the particles to be linked to straight-chain alkanes.

[0284] In one possible implementation, the particles and the connecting base are covalently connected.

[0285] In another optional embodiment, the bond is a covalent bond realized via an amino group, as presented in Formula IV:

[0286]

[0287] Formula IV

[0288] In some other embodiments, the invention envisions an apparatus comprising at least one conjugate having the structural formula V, wherein n is 15, m is an integer between 5 and 10, x is 0, and A is a sulfonic acid:

[0289]

[0290] Formula V

[0291] This invention provides at least one device comprising at least one conjugate. As used herein, a conjugate refers to a compound consisting of several elements (components) including at least one particle, at least one linker, and at least one trapping agent or any derivative thereof or the like, wherein the trapping agent is specifically a trapping agent for ammonia, and in some embodiments may be a sulfonic acid, all of which are associated with the conjugate. It should be noted that although this application relates to "at least one particle," any solid carrier applicable to the various conjugates protected by the claims is covered herein.

[0292] Any conjugate or any composition thereof of the apparatus disclosed herein may also be referred to as a material composition. In the most general sense, a "material composition" similar to "conjugate" (the two terms are used interchangeably) refers to the association of at least one particle, at least one linker and at least one trapping agent, its derivative or the like, as detailed below, the resulting properties of which can be attributed to the material composition (or conjugate) as a whole, rather than any individual conjugate component in a separate state.

[0293] In some embodiments, any conjugate of the device disclosed in this invention comprises the association of at least one particle with at least one chemically reactive portion as a linker, and the association of at least one linker with at least one trapping agent (specifically sulfonic acid) and its derivatives or the like, such that the linker is positioned between the particle and the trapping agent, its derivatives or the like, thus associating with the particle at one end (on one arm) and with the trapping agent, its derivatives or the like at the other end (on a second different arm).

[0294] In some embodiments, the trapping agent (specifically a sulfonic acid) and its derivatives bind specifically and selectively to a particular target, in this case at least one amine (e.g., ammonia), and are capable of effectively trapping, immobilizing, distributing, and removing ammonia from liquid substances (specifically body fluids).

[0295] As used herein, the term “association” or any linguistic variant thereof refers to a chemical or physical force that holds two entities (e.g., particles and connecting groups) together. Such a force can be any type of chemical or physical bonding interaction known to those skilled in the art.

[0296] Non-limiting examples of such associative interactions include covalent bonding, ionic bonding, coordination bonding, complexation, hydrogen bonding, van der Waals bonding, hydrophobic-hydrophilic interactions, etc. Therefore, the association / conjugation of the linker to at least one particle and the association / conjugation of the linker to the trapping agent can be achieved via any chemical bonding, including covalent bonding, electrostatic interactions, acid-base interactions, van der Waals interactions, etc. As understood, the association of the particle to the linker and the association of the linker to the trapping agent, its derivatives, or analogues can be the same or different, as further detailed below.

[0297] The particles of the present invention may include any polymer particles capable of incorporating the linker of the present invention.

[0298] In some embodiments, the particles of the device disclosed in this invention are resin beads.

[0299] As used herein, the term "particle" refers to a substance whose surface can be attached to a chemical or biological compound, a macromolecule, or a portion thereof, via covalent or non-covalent bonding. Particles may comprise porous materials. Particles may be, for example, "spherical" (generally referring to a geometry that is substantially (almost) spherical) or "non-spherical" (having a "long and thin" shape with defined long and short axes). Non-limiting examples of particles include beads, such as at least one of the following: polysaccharide beads, glass beads, cotton beads, plastic beads, nylon beads, latex beads, magnetic beads, paramagnetic beads, superparamagnetic beads, starch beads, etc., silicon beads, PTFE beads, polystyrene beads, gallium arsenide beads, gold beads, or silver beads. In some embodiments, particles are beads including agarose beads, optionally having different degrees of crosslinking at different material (agarose) % percentages.

[0300] Therefore, agarose beads encompass beads containing agarose with varying degrees of cross-linking, such as beads called Sepharose beads. In some embodiments, the beads comprise agarose beads. In some embodiments, the beads comprise Sepharose beads. In some embodiments, the multiple conjugates comprise a combination of particles containing both agarose beads and Sepharose beads. According to this disclosure, it should be noted that particles containing either agarose beads or Sepharose beads are considered as two different conjugates with different particle sizes.

[0301] Sepharose is the trade name for cross-linked beaded agarose, a polysaccharide polymer material extracted from seaweed. Its brand name derives 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 chemical properties of Sepharose are available.

[0302] The particles of the device described herein, specifically beads, can associate with a chemically reactive portion (referred to herein as a linker). The linker, as used herein, can be any chemical entity composed of any combination of atoms, including oligomer chains and polymer chains of any length, and according to some embodiments, the linker is capable of binding to one end of the particle and to at least one trapping agent, its derivative, or the like at the other end.

[0303] In some embodiments, the beads can associate with a linker via a spacer group or coating present on the beads. Thus, the beads are initially activated by association with the spacer group / coating (“activated beads”) and then react with the linker group. It should be noted that sometimes, in cases where the spacer group / coating is directly bound to at least one trapping agent, a linker group may not be necessary. Sometimes, the beads lack functional groups capable of binding to the linker group, and therefore a spacer group or coating can be used.

[0304] Activated beads are obtained by pre-coating the beads with a suitable material having an active portion that enables binding to the beads as well as to linkers and / or traps. In other words, the beads are pre-coated to include reactive groups that enable covalent bonding to linkers or traps.

[0305] In some embodiments, the beads of the conjugate of the device disclosed in this invention can be activated, for example, by pre-coating with any coating material. Non-limiting examples of such materials include, for example, amino acids, proteins, epoxy resins, toluenesulfonyl groups, carboxylic acids, and carboxylated polyvinyl alcohol. When referred to as "pre-coating," it should be understood as a preliminary step of coating the beads with an active material that enables the beads to covalently bind with sulfonic acids (i.e., directly) or via at least one linker. In some embodiments, the beads of the conjugate of the device disclosed in this invention are pre-coated with amino acids, peptides, or any derivatives thereof. The pre-coated magnetic beads may contain, for example, primary amines (–NH2), carboxyl groups (–COOH), mercapto groups (–SH), or carbonyl groups (-CHO) as active groups. In some embodiments, the beads of the conjugate of the device disclosed in this invention are pre-coated to include a portion that can react with primary or secondary amino groups. In some other embodiments, the magnetic beads are coated with polylysine.

[0306] As used herein, the term “connecting base” encompasses any spacer base or pre-coating present on the beads.

[0307] In some embodiments, the linker is or comprises an atomic chain, such as a straight chain. In some embodiments, the linker comprises at least 1 atom, at least 4 atoms, sometimes 5 atoms, sometimes 10 atoms, sometimes 20 atoms, sometimes 30 atoms, and sometimes 40 atoms. In some embodiments, the linker is or comprises a straight chain of 1 to 40 atoms. In some embodiments, the linker is or comprises a straight chain of 1 atom. In some embodiments, the linker is a straight chain comprising 5 atoms. In some embodiments, the linker is a straight chain comprising 15 atoms.

[0308] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads; therefore, in some embodiments, the resin beads are agarose resin, which may contain between about 2% and 10% agarose. Further, in some embodiments, the resin beads may contain between 3% and 9% agarose, and even further, in some embodiments, the resin beads may contain between 4% and 8% agarose. According to any more specific, non-limiting embodiment, the resin beads contain at least 4% agarose. In some other embodiments, the amount of agarose in the particles of the conjugate of the apparatus disclosed in this invention is at least 5%, and sometimes at least 6%.

[0309] In some embodiments, the conjugates of the apparatus of this disclosure comprise particles with an average particle size between about 10 µm and about 500 µm. Specifically, 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 larger. In some specific embodiments, the multiple conjugates comprise particles with 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 apparatus disclosed in this invention exhibit an average particle size between about 40 µm and about 170 µm.

[0310] The terms "average size," "average diameter," or "mean size" refer to the arithmetic mean of measured diameters, where the diameter is within ±25% of this average. The mean size of the particles can be measured by any method known in the art. In some embodiments, the size of the resin beads is between 40 µm and 170 µm, where the average size is between about 80 µm and about 100 µm. Sometimes, the average size is 90 µm.

[0311] As noted above, according to this aspect of the invention, the present invention relates to an apparatus and system, particularly for enabling the depletion of ammonia from biological fluids.

[0312] See Figure 1 and Figure 2 The device, generally referred to as 100, according to a first embodiment of the subject matter disclosed in the present invention, includes a housing 200 and an active material 300 contained therein.

[0313] Housing 200 includes outer casing 230, inlet end cap 222, and outlet end cap 224. Housing 200 defines a longitudinal axis LA.

[0314] The housing 230 extends longitudinally between the inlet end 212 and the outlet end 214. At least in this example, the housing is generally cylindrical.

[0315] The chamber 250 is defined between the housing 230, the inlet end 212 and the outlet end 214, and the chamber 250 provides a controlled volume CV that can be filled with active material 300.

[0316] In at least this example, the inlet end cap 222 is configured to be hermetically installed to the inlet end 212, and the outlet end cap 224 is configured to be hermetically installed to the outlet end 214.

[0317] At least in this example, the inlet end cap 222, the outlet end cap 224, and the housing 230 are each made of a suitable medically compatible material, such as Terlux HD 2802 supplied by Ineos or Makrolon 2458 supplied by Covestro.

[0318] At least in this example, particularly referring to Figures 3(a), 4(a) through 4(d), the inlet end cap 222 includes a corresponding enlarged portion 222A with an inner diameter sufficient to allow the corresponding enlarged portion 222A to engage with the corresponding engaging portion 212A at the inlet end 212 in an overlapping relationship. The free end 222B of the corresponding enlarged portion 222A includes a generally annular flat surface 222C.

[0319] Similarly, at least in this example, with particular reference to Figures 3(a), 5(a) through 5(d), the outlet end cap 224 includes a corresponding enlarged portion 224A with an inner diameter sufficient to allow the corresponding enlarged portion 224A to engage with the corresponding engaging portion 214A in an overlapping relationship at the outlet end 214. The free end 224B of the corresponding enlarged portion 224A includes a generally annular flat surface 224C.

[0320] At least in this example, with particular 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 corresponding internally threaded walls 222X and 224X, which are complementary to corresponding externally threaded walls 232 and 234 provided at the inlet end 212 and the outlet end 214, respectively. Optionally, an external sealing strip and / or an internal O-ring (not shown) may be provided to provide additional sealing between the respective inlet end cap 222 and / or outlet end cap 224 and the housing 230.

[0321] Furthermore, at least in this example, the inlet end cap 222 and the outlet end cap 224 are each configured as self-locking end caps relative to the housing 230, such that the respective inlet end cap 222 and / or outlet end cap 224 can be locked in place in a sealing manner relative to the housing 230.

[0322] Therefore, at least in this example, see also Figure 6 and Figure 7 The device 100 (particularly housing 200) includes a first self-locking arrangement 280 and a second self-locking arrangement 290, wherein the first self-locking arrangement is configured to enable the inlet end cap 222 to self-lock relative to the housing 230, and the second self-locking arrangement is configured to enable the outlet end cap 224 to self-lock relative to the housing 230.

[0323] See you again Figure 6 The first self-locking arrangement 280 includes a plurality of first wedge elements 282 disposed in the inlet end cap 222, which cooperate with the first flange stop arrangement 260 to provide self-locking of the inlet end cap 222 relative to the housing 230. Although in this embodiment the inlet end cap 222 includes two first wedge elements 282, in alternative variations of this example the inlet end cap 222 may include one or more first wedge elements.

[0324] Each first wedge element 282 protrudes away from the corresponding annular flat surface 222C in the longitudinal direction. Furthermore, the first wedge elements 282 are equidistant from each other in the circumferential direction along the corresponding annular flat surface 222C.

[0325] At least in this example, each first wedge element 282 is a right-angled wedge shape, comprising a corresponding first wedge edge 283 and a corresponding second wedge edge 284, which intersect at a corresponding wedge vertex 285. The wedge vertex 285 is at a first wedge height WH1 relative to the annular flat surface 222C. Each first wedge element also has a first base dimension BD1 at the annular flat surface 222C.

[0326] The first wedge-shaped edge 283 is inclined at an acute angle α relative to the corresponding annular flat surface 222C. At least in this example, the angle α is significantly less than 90°, for example, in the range between about 5° and about 30°, such as about 20°.

[0327] The second wedge edge 284 is inclined approximately orthogonally to the corresponding annular flat surface 222C. As will become clearer here, the second wedge edge 284 engages with the first flange stop arrangement 260 to enable the inlet end cap 222 to self-lock relative to the housing 230.

[0328] The first flange stop arrangement 260 includes a first annular flange 262 disposed on the outer surface 232 of the housing 230 and longitudinally spaced from the inlet end 212 by a first distance X1. The first annular flange has a corresponding first annular surface 263 and a corresponding second annular surface 264 facing in the opposite direction. The first annular surface 263 faces the inlet end 212, and therefore the first annular surface 263 is spaced from the inlet end 212 by the first distance X1.

[0329] The first spacing X1 is sufficient to ensure that, for example, when the inlet end cap 222 is fully engaged with the housing 230 (at least in this example, by screwing the inlet end cap 222 relative to the housing 230), the corresponding annular flat surface 222C at the corresponding free end 222B is in abutment contact with the annular surface 263.

[0330] The first flange stop arrangement 260 also includes a plurality of first stop elements 268 corresponding to the plurality of first wedge elements 282. Thus, at least in this example, the first flange stop arrangement 260 includes two first stop elements 268 corresponding to the two first wedge elements 282.

[0331] At least in this embodiment, each first stop element 268 is shaped as a corresponding abutment surface 268A disposed in the first annular flange 262. The first annular flange 262 thus includes cutouts 267 corresponding to the first wedge elements 282, and each cutout 267 has a circumferential length and axial depth respectively at least equal to the first base dimension BD1 and the first wedge height WH1 of each first wedge element 282, so that the corresponding first wedge element 282 can be accommodated therein, and has a corresponding abutment surface 268A for abutting with the corresponding second wedge edge 284.

[0332] Therefore, when the inlet end cap 222 is screwed onto the first inlet end 212 of the housing 230 in the engagement rotation direction, the first wedge element 282 eventually abuts against the first annular surface 263. As the inlet end cap 222 is further screwed onto the first inlet end 212 of the housing 230, the portion of the first wedge element 282 and / or the first annular flange 262 that contacts it is slightly deformed until the corresponding first wedge element 282 snaps into the corresponding cutout 267 via the corresponding first wedge edge 283. Thereafter, the corresponding second wedge edge 284 abuts against the corresponding abutment surface 268A, thereby preventing relative rotation between the inlet end cap 222 and the housing 230 in the disengagement direction.

[0333] In an alternative variation of this implementation, the first flange stop arrangement 260 can be of a different form. For example, the first flange 262 can be replaced by multiple mechanical stops, each of which includes a boss projecting radially from the housing 230. Each such mechanical stop corresponds to a different one of the first wedge elements 282 and is located at a corresponding position on the outer surface of the housing 230, corresponding to the position of the corresponding first wedge element 282 when the inlet end cap 222 is fully screwed into place. Each such boss includes a corresponding abutment surface for abutting relative to a corresponding second wedge edge 284.

[0334] See you again Figure 7 The second self-locking arrangement 290 includes a plurality of second wedge elements 292 disposed in the outlet end cap 224, which cooperate with the second flange stop arrangement 270 to provide self-locking of the outlet end cap 224 relative to the housing 230. Although in this embodiment, the outlet end cap 224 includes two second wedge elements 292, in alternative variations of this example, the outlet end cap 224 may include one or more second wedge elements.

[0335] Each second wedge element 292 protrudes away from the corresponding annular flat surface 224C in the longitudinal direction. Furthermore, the second wedge elements 284 are equidistant from each other in the circumferential direction along the corresponding annular flat surface 224C.

[0336] At least in this example, each second wedge element 292 is a right-angled wedge shape, comprising a corresponding first wedge edge 293 and a corresponding second wedge edge 294, which intersect at a corresponding wedge vertex 295. The wedge vertex 295 is at a second wedge height WH2 relative to the annular flat surface 224C. Each second wedge element 292 also has a second base dimension BD2 at the annular flat surface 224C.

[0337] The corresponding first wedge edge 293 is inclined at an acute angle β relative to the corresponding annular flat surface 224C. At least in this example, the angle β is significantly less than 90°, for example, in the range between about 5° and about 30°, such as about 20°.

[0338] The corresponding second wedge edge 294 is inclined approximately orthogonally to the corresponding annular flat surface 224C. As will become clearer here, the second wedge edge 294 engages with the second flange stop arrangement 270 to enable the outlet end cap 224 to self-lock relative to the housing 230.

[0339] The second flange stop arrangement 270 includes a corresponding first annular flange 272 disposed on the outer surface 232 of the housing 230 and longitudinally spaced from the outlet end 214 by a second distance X2. The second annular flange 272 has a corresponding first annular surface 273 and a corresponding second annular surface 274 facing in the opposite direction. The first annular surface 273 faces the outlet end 214, and therefore the corresponding first annular surface 273 is spaced from the outlet end 214 by the second distance X2.

[0340] The second spacing X2 is sufficient to ensure, for example, that the corresponding annular flat surface 224C at the corresponding free end 224B is in abutment contact with the annular surface 273 when the outlet end cap 224 is fully engaged with the housing 230 (at least in this example, by screwing the outlet end cap 224 relative to the housing 230).

[0341] The second flange stop arrangement 270 also includes a plurality of second stop elements 278 corresponding to the plurality of second wedge elements 292. Thus, at least in this example, the second flange stop arrangement 270 includes two second stop elements 278 corresponding to the two second wedge elements 292.

[0342] At least in this embodiment, each second stop element 278 is shaped as a corresponding abutment surface 278A disposed in the second annular flange 272. The second annular flange 272 thus includes cutouts 277 corresponding to the second wedge elements 292, and each cutout 277 has a circumferential length and axial depth respectively at least equal to the second base dimension BD2 and the second wedge height WH2 of each second wedge element 292, so that the corresponding second wedge element 292 can be accommodated therein and has a corresponding abutment surface 278A for abutting relative to the corresponding second wedge edge 294.

[0343] Therefore, when the outlet end cap 224 is screwed onto the outlet end 214 of the housing 230 in the engagement rotation direction, the second wedge element 292 eventually abuts against the corresponding first annular surface 273. As the outlet end cap 224 is further screwed onto the outlet end 214 of the housing 230, the portion of the second wedge element 292 and / or the second annular flange 272 that contacts it is slightly deformed until the corresponding second wedge element 292 snaps into the corresponding cutout 277 via the corresponding first wedge edge 293. Thereafter, the corresponding second wedge edge 294 abuts against the corresponding abutment surface 278A, thereby preventing relative rotation between the outlet end cap 224 and the housing 230 in the disengagement direction.

[0344] In an alternative variation of this embodiment, the second flange stop arrangement 270 can be of different forms. For example, the second annular flange 272 can be replaced by multiple mechanical stops, each of which includes a boss projecting radially from the housing 230. Each such mechanical stop corresponds to a different one of the second wedge elements 292 and is located at a corresponding position on the outer surface of the housing 230, corresponding to the position of the corresponding second wedge element 292 when the outlet end cap 224 is fully screwed into place. Each such boss includes a corresponding abutment surface for abutting relative to the corresponding second wedge edge 294.

[0345] However, in alternative variations of this example, different configurations can be provided for hermetically mounting the inlet end cap 222 and / or the outlet end cap 224 to the housing 230.

[0346] Therefore, at least according to this embodiment, the inlet end cap 222 and / or the outlet end cap 224 facilitate the process of filling the control volume CV with active material 300. One of the inlet end cap 222 and the outlet end cap 224 is sealed to the housing 230, thereby keeping 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 via the open outlet end 214 or inlet end 212. Thereafter, the chamber 250 can 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, and this allows for the simple formation of a dome, typically manually, without requiring special equipment, and without obstructing or damaging the active material 300 in the control volume CV.

[0347] See also Figure 1 At least in this embodiment, the device 100 includes a fluid inlet port 210 and a fluid outlet port 220. However, in alternative variations of this embodiment, the device may have more than one fluid inlet port and / or more than one fluid outlet port. In any case, both the fluid inlet port 210 and the fluid outlet port 220 are in fluid communication with the chamber.

[0348] In at least this example, the fluid inlet port 210 is located in the inlet end cap 222, and the fluid outlet port 220 is located in the outlet end cap 224.

[0349] See you again Figure 2 In at least in this example, the device also includes a first barrier member 310 at the inlet end 212 and a second barrier member 320 at the outlet end 214.

[0350] Each of the first barrier member 310 and the second barrier member 320 is configured to allow fluid (especially liquid plasma) to flow through the corresponding barrier member in one direction, while preventing fluid (especially liquid plasma) from flowing through the corresponding barrier member in the opposite direction. Thus, each of the first barrier member 310 and the second barrier member 320 functions as a corresponding one-way valve.

[0351] The first barrier member 310 and the second barrier member 320 are oriented in the device 100 to allow fluid (especially liquid plasma) to flow from the fluid inlet port 210 through the device 100 in one direction to the fluid outlet port 220, while simultaneously blocking fluid from flowing in the opposite direction from the fluid outlet port 220 through the device 100 to the fluid inlet port 210.

[0352] See also Figure 2 and Figure 8 At least in this example, the first barrier member 310 is disposed in the first barrier member assembly 319 and includes a disc-shaped membrane member 312 made of a suitable medically compatible material, such as polyethersulfone (PES), with a pore size of, for example, 15 µm, a thickness of, for example, 145.7 µm, and a diameter of approximately 44.5 mm. In the first barrier member assembly 319, the membrane member 312 is fixedly held between a corresponding first ring 313 and a corresponding second ring 314, and is housed in an annular washer member 315 having a U-shaped cross-section. Referring also to FIG. 4(b), the enlargement 222A includes an inner shoulder 222D located between a corresponding internally threaded wall 222X and a fluid inlet port 210, in which the first barrier member assembly 319 is mounted.

[0353] Similarly, see also Figure 2 and Figure 9 At least in this example, the second barrier member 320 is disposed within the second barrier member assembly 329 and includes a disc-shaped membrane member 322 made of a suitable medically compatible material, such as polyethersulfone (PES), with a pore size of, for example, 15 µm, a thickness of, for example, 145.7 µm, and a diameter of approximately 44.5 mm. In the second barrier member assembly 329, the membrane member 322 is fixedly clamped between a corresponding first ring 323 and a corresponding second ring 324, and housed within an annular washer member 325 having a U-shaped cross-section. Referring also to FIG. 5(b), the enlargement 224A includes an inner shoulder 224D located between a corresponding internally threaded wall 224X and a fluid outlet port 220, in which the second barrier member assembly 329 is mounted.

[0354] In alternative variations of this and other examples, these barrier components may include, for example, filters comprising a fiber or plastic substrate, wherein ligands are conjugated to the fiber or plastic substrate, wherein the ligands are conjugated; or, for example, other suitable membranes, such as unidirectional membranes that allow bodily fluids to flow through in one direction without flowing in the opposite direction.

[0355] Referring specifically to Figure 3(c), the control volume CV is surrounded and limited by the first barrier member 310, the second barrier member 320, and the inner surface 235 of the outer casing 230.

[0356] At least in this example, specifically referring to Figure 3(a), the longitudinal length L1 of the housing 200 is between about 200 mm and about 210 mm, for example, 205 mm.

[0357] At least in this example, the outer diameter D1 of the housing 200 is between about 40 mm and about 50 mm, for example 48.8 mm.

[0358] Referring to Figure 3(c), at least in this example, the longitudinal length L2 of the chamber 250 (specifically the control volume CV) is between about 200 mm and about 210 mm, for example 205 mm, and its diameter D2 is between about 40 mm and about 45 mm, for example 42.8 mm.

[0359] At least in this example, the controlled volume CV of chamber 250 is between approximately 257 ml and 326 ml, for example 306 ml, for containing active material 300.

[0360] For this aspect of the subject matter disclosed in the invention, see [link to relevant documentation]. Figure 10 It also provides a system 700 for enabling the depletion of ammonia from a biological fluid, which includes at least one device 100, a blood component apheresis machine 900 (including a pool or blood mixing reservoir 890 and a separation system 870, such as including a centrifuge and a pump), and a catheter system 800.

[0361] The apheresis blood component machine 900 is configured to receive blood from the body of a subject in need (referred to herein as BD) via a catheter system 800, and to separate the received blood into its various components: plasma, platelets, white blood cells, and red blood cells. Many examples of commercially available apheresis blood component machines are known, such as the Terumo BCT Spectra Optia apheresis blood component system. The apheresis blood component machine 900 is also configured to return the processed blood to the body of the subject in need (BD) via the catheter system 800 after processing by device 100.

[0362] A blood mixing reservoir 890 (integrated with the apheresis component machine 900 at least in this example) is configured to receive plasma processed by device 100, and blood products (e.g., platelets, white blood cells, and red blood cells, as well as some raw plasma) separated from the plasma by the separation system 870 of the apheresis component machine 900. The blood mixing reservoir 890 is also configured to enable the mixing of the received processed plasma and blood products to provide processed blood.

[0363] The catheter system 800 includes a first catheter 810 that provides selective fluid communication between the apheresis component machine 900 and the body BD of the subject in need, allowing blood to flow from the body BD of the subject in need to the apheresis component machine 900.

[0364] The catheter system 800 includes a second catheter 820 that provides fluid communication from the plasma outlet 910 of the apheresis component machine 900 to the fluid inlet port 210 of the device 100, so that plasma separated from blood by the apheresis component machine 900 can flow into the device 100.

[0365] The catheter system 800 includes a third catheter 830 that provides fluid communication from the fluid outlet port 220 of the device 100 via port 920 to the blood mixing reservoir 890 of the apheresis component machine 900, so that the processed plasma processed by the device 100 can flow into the blood mixing reservoir 890.

[0366] The catheter system 800 includes a fourth catheter 840 (within the apheresis blood component machine 900) that provides fluid communication from the blood product outlet of the separation system 870 of the apheresis blood component machine 900 to the blood mixing reservoir 890, so that other products separated from the plasma by the separation system 870 of the apheresis blood component machine 900 can flow into the blood mixing reservoir 890.

[0367] The catheter system 800 includes a fifth catheter 850 that provides selective fluid communication between the blood mixing reservoir 890 of the apheresis component machine 900 and the body BD of the subject in need, so that processed blood can flow from the blood mixing reservoir 890 of the apheresis component machine 900 to the body BD of the subject in need.

[0368] Therefore, during the operation of system 700, system 700 is connected to the body BD of the subject in need via catheter system 800 (particularly via first catheter 810 and fifth catheter 850).

[0369] Before connecting the system 700 to the body BD of the subject in need, the system 700 is perfused with a suitable fluid (e.g., saline solution) using an appropriate perfusion procedure.

[0370] The apheresis blood component machine 900 is operated to separate incoming blood from the body BD of the subject in need into plasma and blood products. The plasma is guided to the device 100 via a second conduit 820, while other blood products separated by the apheresis blood component machine 900 are guided to the blood mixing reservoir 890 of the apheresis blood component machine via a fourth conduit 840.

[0371] The plasma is processed in device 100, and the processed plasma is guided via third conduit 830 to the blood mixing reservoir 890 of apheresis component machine 900.

[0372] Subsequently, the processed blood is guided from the blood mixing reservoir 890 of the apheresis component machine 900 to the body of the subject in need via the fifth catheter 850.

[0373] In alternative variations of this implementation scheme, see, for example, [link to relevant documentation]. Figure 11 The blood mixing reservoir 890 is separate from the apheresis blood component machine 900, and the blood mixing reservoir 890 is connected to the apheresis blood component machine 900, the device 100 and the body BD via separate fourth catheter 840, third catheter 830 and fifth catheter 850 respectively.

[0374] It should be noted that in alternative variations of these implementations, the corresponding system 700 may include multiple such devices 100, such as a series of such devices 100, which are connected to the corresponding apheresis blood component machine 900, blood mixing reservoir 890 and catheter system 800.

[0375] For example, see some such examples. Figure 12 Multiple such devices 100 (e.g., in such devices of series 100A) can be connected in series with each other, such that the fluid outlet port 220 of the first device is connected to the fluid inlet port 210 of the next device 100 (directly or via a conduit), and similar connections are provided along these series-arranged devices 100, wherein the fluid outlet port 220 of the last device 100 is connected to the blood mixing reservoir 890 via a corresponding third conduit 830. This arrangement allows for further processing of the plasma before it is returned to the subject in need via a corresponding fifth conduit 850.

[0376] For example, see in some other such examples. Figure 13Multiple such devices 100 (e.g., in the series 100B) can be connected in parallel relative to each other, such that a first conduit 810 is simultaneously connected to the fluid inlet port 210 of all these devices, for example via a first manifold 825. Similarly, the fluid outlet ports 220 of all these devices 100 are simultaneously connected to a third conduit 830, and thus to a blood mixing reservoir 890, for example via a second manifold 835. This arrangement allows for the simultaneous processing of larger volumes of blood.

[0377] For example, in some other examples, see Figure 14 Such multiple devices 100 (e.g., in such devices of series 100C) can be interconnected both in parallel and in series, that is, these devices are divided into multiple groups 100G, with the devices 100 in each group 100G connected in series with each other, while the multiple groups 100G are connected 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 to the fluid inlet port 210 of the next device 100 (directly or via a pipe).

[0378] In at least this example, the active material 300 comprises at least one of the following: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates. More specifically, the conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0379]

[0380] Formula I

[0381] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. In some optional embodiments, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0382] It should be understood that the physical condition of the required subjects (as discussed in this article) Figures 10 to 14 The term "subject" (also referred to as "BD") refers to any mammalian subject requiring such treatment. In some embodiments, the subject (also referred to as "patient" in some embodiments herein) is a subject who has or exhibits elevated blood ammonia levels, and / or a subject who suffers from any disorder and / or condition associated with elevated blood ammonia levels (e.g., hyperammonemia) and any condition and disorder disclosed in this disclosure in conjunction with other aspects thereof.

[0383] In some embodiments, the apparatus of this disclosure can be used to deplete at least one amine from at least one liquid substance.

[0384] In some other specific embodiments, the amine depleted by the apparatus of this disclosure is ammonia. In some other embodiments, the liquid substance is mammalian body fluid. Therefore, the apparatus of this disclosure is used to deplete ammonia from mammalian body fluid.

[0385] In some embodiments, the conjugate contained in the device is any conjugate as defined in this disclosure.

[0386] In some specific embodiments, the conjugate of the device of the present invention has the structural formula V. More specifically, the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising 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 mth carbonyl group.

[0387]

[0388] Formula V

[0389] Where m is an integer between 5 and 10. In some embodiments, the linker comprises a chain of 15 carbon atoms covalently bonded to 5 to 10 carbonyl groups (specifically, 5, 6, 7, 8, 9, 10 or more carbonyl groups).

[0390] In some other embodiments, the apparatus of this disclosure is configured to contain at least about 50 ml to about 500 ml of the conjugates disclosed herein, or any plurality of conjugates or combinations thereof, specifically about 50 ml, 55 ml, 60 ml, 65 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 20 ml, etc. 0 ml, 210 ml, 220 ml, 230 ml, 240 ml, 250 ml, 260 ml, 270 ml, 280 ml, 290 ml, 300 ml, 310 ml, 320 ml, 330 ml, 340 ml, 350 ml, 360 ml, 370 ml, 380 ml, 390 ml, 400 ml, 410 ml, 420 ml, 430 ml, 440 ml, 450 ml, 460 ml, 470 ml, 480 ml, 490 ml, 500 ml. In some other embodiments, the apparatus of this disclosure is configured to contain a volume of at least about 250 ml to 350 ml, specifically 270 ml to 300 ml of the conjugate disclosed herein.

[0391] As will become clearer herein, the device is configured to deplete at least one type of ammonia from the bodily fluids of mammals (e.g., human plasma and / or human whole blood, and / or plasma and / or whole blood of other mammals), as an example of processing mammalian bodily fluids. More specifically, the device disclosed herein is configured to deplete, reduce, or distribute ammonia from bodily fluids.

[0392] The term "partition" in relation to a target compound (specifically, at least one amine, and more specifically, ammonia) refers to the separation of ammonia from the remainder of a liquid substance (specifically, blood fluid) to provide an ammonia-free body fluid or any other liquid substance. Therefore, the term "partition" encompasses the depletion and removal of at least one amine (more specifically, ammonia) from a liquid substance (specifically, body fluid). As used herein, the term "depletion" is defined as the removal of ammonia from a liquid substance (specifically, body fluid) to a certain extent in order to obtain an ammonia-depleted or reduced liquid substance (specifically, body fluid). More specifically, as used herein, the term “clearance” or “depletion” achieved by distributing or capturing at least one amine (specifically, ammonia) means limiting, reducing, lowering, or shrinking the amount of at least one amine (specifically, ammonia) in a liquid matrix or body fluid by 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%. The restriction, delay, reduction, decrease, or reduction of the amount of at least one amine (specifically, ammonia) in a liquid substance (specifically, body fluids) is also 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%, 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%.

[0393] In some other embodiments, the apparatus of this 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 apparatus of this invention is particularly suitable for depleting ammonia from at least about 100 ml to at least about 10 liters of bodily fluid, the volume of which is specifically 100 ml, 200 ml, 300 ml, 400 ml, 500 ml, 600 ml, 700 ml, 800 ml, 900 ml, 1000 ml, 1100 ml, 1200 ml, 1300 ml, 1400 ml, 1500 ml, 1600 ml, 1700 ml, 1800 ml, 1900 ml, 2000 ml, 2100 ml, 2200 ml, 2300 ml, 2400 ml, 25 ... 00ml, 2600ml, 2700ml, 2800ml, 2900ml, 3000ml, 3100ml, 3200ml, 3300ml, 3400ml, 3500ml, 3600ml, 3700ml, 3800ml, 3900ml, 4000ml, 4100ml, 4200ml, 4300ml, 4400ml, 4500ml, 4600ml, 4700ml, 4800ml, 4900ml, 5000ml, more specifically 5.5L, 6L, 6.5L, 7L, 7.5L, 8L, 8.5L, 9L, 9.5L, 10L.

[0394] Another aspect provided in this disclosure relates to a battery for depleting ammonia from the bodily fluids of a mammal, comprising a plurality of devices as defined in this disclosure.

[0395] Another aspect relates to an in vitro device comprising at least one conjugate, or at least one device comprising the conjugate. In some embodiments, the in vitro device may be connected to at least one such device or a series of such devices. In a more specific embodiment, the conjugate of the in vitro device disclosed herein may comprise particles bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0396]

[0397] Formula I

[0398] Wherein, 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 trapping agent A is characterized by having the ability to trap or bind amines, optionally, the amine being at least one of methylamine, dimethylamine, or trimethylamine. In some further embodiments, the device included in or connected to an external device may include:

[0399] - A housing having at least one fluid inlet port and at least one fluid outlet port;

[0400] The housing includes at least one chamber defining a control volume 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 substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates.

[0401] In some embodiments, conjugates, multiple conjugates or compositions, devices for external devices, and batteries are as defined in this disclosure.

[0402] In some embodiments, the extracorporeal device of this disclosure is suitable for depleting ammonia from the bodily fluids of mammals.

[0403] In some other embodiments, the in vitro device of this disclosure is adapted to deplete, remove, and reduce at least one amine (specifically, ammonia) from at least one volume of liquid substance. More specifically, in some embodiments, the in vitro device disclosed herein 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, between about 2 liters and 3 liters of body fluid).

[0404] In another aspect, the present invention provides a conjugate having structural formula I, the conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0405]

[0406] Formula I

[0407] Where 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 trapping agent A is characterized by having the ability to trap or bind amines. As noted above, in some embodiments, the linker group comprises 5 to 15 carbon atoms. In some embodiments, since the length of a carbon atom is about 1.5 angstroms, the length of the linker group can be in the range of less than 7.5 angstroms to more than 22.5 angstroms. In still other embodiments, the linker group further comprises between 5 and 10 carbonyl groups. Since the length of each carbonyl group can be about 1.3 angstroms, its length can be in the range of less than about 6.5 angstroms to more than 13 angstroms.

[0408] In other words, this disclosure provides a conjugate comprising three parts:

[0409] -Particles;

[0410] - Connecting base; and

[0411] -Collecting agent.

[0412] These three parts are connected to each other by connecting groups that link the particles and the trapping agent.

[0413] The linker of the present invention typically includes two groups, wherein the first group includes straight-chain alkanes containing n carbon atoms, and the second group includes m covalently bonded carbonyl groups.

[0414] In some embodiments, the linear alkane of the linker group of the conjugate disclosed herein is saturated or unsaturated.

[0415] In some embodiments, the straight-chain alkane group may be saturated, while in other embodiments, the group may be unsaturated.

[0416] In embodiments where the straight-chain alkane group is unsaturated, the chain may contain between one and three double bonds.

[0417] The trapping agent portion designated as A in this document may include any reagent having the ability to "capture" or bind amines.

[0418] In the context of this disclosure, the term "amine" refers to any compound or functional group containing at least one basic nitrogen atom and at least one lone pair of electrons. Amines according to this disclosure may include any primary, secondary, and tertiary amines with a molecular weight (MW) between at least 17 Daltons and at most 70 Daltons.

[0419] In some embodiments, the amine is an alkylamine, dialkylamine, or trialkylamine, wherein the molecular weight (MW) of such amine is between 17 Daltons and 70 Daltons.

[0420] In some other embodiments, the amine is selected from methylamine, dimethylamine, or trimethylamine.

[0421] In one specific implementation, the amine is ammonia.

[0422] The linker of the present invention uses the m-th carbonyl group via a straight bond ( ) or linked through another short alkane chain ( X is covalently attached to the trap in the manner of X, where X is an integer in the range of 1 to 3.

[0423] In some embodiments, the trapping agent can be any ion exchange material. More specifically, since ammonia is a cation at physiological pH, it can bind to cation exchangers. Other alternatives covered by this invention include NHS and epoxy resins.

[0424] In some implementations, the trapping agent is an acid.

[0425] In some implementations, the acid is a strong acid capable of capturing amines.

[0426] In some implementations, the amine is as defined above.

[0427] In some other implementations, the amine is ammonia.

[0428] In the context of the disclosure provided herein, the term “strong acid” is any acid with a pKa value less than 1.

[0429] pKa is sometimes below 0, sometimes below (-1), sometimes below (-2), sometimes below (-3), sometimes below (-4), sometimes below (-5), sometimes below (-6), sometimes below (-7), sometimes below (-8), and sometimes below (-9).

[0430] 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, analogs thereof, and derivatives thereof.

[0431] In one specific implementation, the acid is sulfuric acid or a derivative thereof.

[0432] Sulfonic acid derivatives can be any molecule having the following general formula:

[0433]

[0434] R is an organic alkyl or aryl group.

[0435] In the implementation scheme, the sulfonic acid derivative is selected from taurine, PFOS, p-toluenesulfonic acid, and coenzyme M.

[0436] In some implementations, R is -H.

[0437] In the most general terms, the length of the straight-chain alkane determines the specificity of the conjugate. Too long a linker will capture non-specific / unwanted molecules, such as proteins and amino acids (because they contain amino groups). Short linkers will reduce the conjugate's ability to capture ammonia and ammonium cations.

[0438] Therefore, in the implementation scheme, the length (n) of the straight-chain alkane is between 5 and 20 carbon atoms, specifically, between 5 and 19 carbon atoms, between 5 and 18 carbon atoms, between 5 and 17 carbon atoms, between 5 and 16 carbon atoms, between 5 and 15 carbon atoms, between 5 and 14 carbon atoms, between 5 and 13 carbon atoms, between 5 and 12 carbon atoms, and between 5 and 11 carbon atoms. The lengths (n) of the straight-chain alkane are: between 5 and 10 carbon atoms, between 6 and 20 carbon atoms, between 7 and 20 carbon atoms, between 8 and 20 carbon atoms, between 9 and 20 carbon atoms, between 10 and 20 carbon atoms, between 1 and 20 carbon atoms, between 12 and 20 carbon atoms, between 13 and 20 carbon atoms, between 14 and 20 carbon atoms, and between 15 and 20 carbon atoms. In some other embodiments, the length (n) of the straight-chain alkane is sometimes between 10 and 15 carbon atoms, sometimes between 12 and 15 carbon atoms, sometimes between 13 and 15 carbon atoms, and sometimes between 14 and 15 carbon atoms. In some specific embodiments, the length (n) of the straight-chain alkane is 5 or less, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or longer. In one specific and non-limiting embodiment, n is 15.

[0439] Without being bound by theories or mechanisms, the carbonyl moiety provides adequate bulkiness, preventing amino acids and peptides from attaching to the acidic portion of the conjugate. The inventors of this disclosure unexpectedly discovered that between five and ten carbonyl groups bonded together provide sufficient bulkiness to prevent larger molecules from being trapped by the acidic portion of the conjugate.

[0440] Therefore, in embodiments, the conjugates of this disclosure (as mentioned herein in all disclosed structural formulas and all disclosed aspects) comprise between about 5 and 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, 8 to 9. More specifically, 5, 6, 7, 8, 9, or 10 carbonyl groups. In a specific and non-limiting embodiment, m is 5, and according to such embodiments, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 5th carbonyl group. In one specific and non-limiting embodiment, m is 6, and according to such an embodiment, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 6th carbonyl group. In one specific and non-limiting embodiment, m is 7, and according to such an embodiment, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 7th carbonyl group. In one specific and non-limiting embodiment, m is 8, and according to such an embodiment, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 8th carbonyl group. In one specific and non-limiting embodiment, m is 9, and according to such an embodiment, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 9th carbonyl group. In one specific and non-limiting embodiment, m is 10, and according to such an embodiment, a sulfonic acid covalently bonded to the m-th carbonyl group means a sulfonic acid covalently bonded to the 10th carbonyl group.

[0441] It should be understood that, in some embodiments, the conjugates of this disclosure may comprise any combination of any number (m) of carbonyl groups and any number (n) of straight-chain alkanes.

[0442] In other embodiments of the invention, a conjugate is provided comprising particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, the conjugate having structural formula II:

[0443]

[0444] Formula II

[0445] Where x is between 0 and 3.

[0446] When x is 0, the m-th carbonyl group is directly attached to the acid.

[0447] In some other embodiments, the present invention provides a conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, the conjugate having structural formula III:

[0448]

[0449] Formula III

[0450] Where x is between 0 and 3.

[0451] In some implementations, x is between 0 and 2, and sometimes between 0 and 1. Sometimes x is 1, and sometimes x is 0.

[0452] When x is 0, the m-th carbonyl group is directly attached to the acid.

[0453] In some embodiments, the conjugates of this disclosure are configured to act as amine traps, thereby exhibiting a neutralization reaction of the amine. In more specific embodiments, the amine is ammonium.

[0454] Furthermore, in some embodiments, the linker portion of the conjugate disclosed herein is linked to the particle via any suitable functional group that allows the particle to be linked to a straight-chain alkane.

[0455] Unbound by theory or reaction mechanism, the conjugates of the present invention act as amine traps, which exhibit a neutralization reaction of an amine with each acid trap as defined above:

[0456]

[0457] Where -H is the free hydrogen atom of the acid, and (:) is the free electron of the amine.

[0458] In embodiments where the acid is a sulfonic acid and the amine is ammonia, the proton (H) + The following is an example of donating two free electrons to ammonia:

[0459]

[0460] This results in the formation of ionic bonds between the conjugate acid and the conjugate base.

[0461] The linker portion disclosed herein can be linked to particles via any group known in the art, which allows the particles to be linked to straight-chain alkanes.

[0462] In one possible implementation, the particles and the connecting base are covalently connected.

[0463] In another optional embodiment, the bond is a covalent bond realized via an amino group, as presented in Formula IV:

[0464]

[0465] Formula IV

[0466] In some other embodiments, the invention envisions conjugates having the structural formula V, where n is 15, m is an integer between 5 and 10, x is 0, and A is a sulfonic acid:

[0467]

[0468] Formula V

[0469] This invention provides at least one conjugate. As used herein, a conjugate refers to a compound consisting of several elements (components) including at least one particle, at least one linker, and at least one trapping agent or any derivative thereof or the like, wherein the trapping agent is specifically a trapping agent for ammonia, and in some embodiments may be a sulfonic acid, all of which are associated with the conjugate. It should be noted that although this application relates to "at least one particle," any solid carrier applicable to the various conjugates protected by the claims is covered herein.

[0470] Any conjugate or any composition thereof disclosed in this invention may also be referred to as a material composition. In the most general sense, a "material composition" similar to "conjugate" (the two terms are used interchangeably) refers to the association of at least one particle, at least one linker and at least one trapping agent, its derivative or the like, as detailed below, the resulting properties of which can be attributed to the material composition (or conjugate) as a whole, rather than any individual conjugate component in a separate state.

[0471] In some embodiments, any conjugate of the subject matter disclosed in this invention encompasses the association of at least one particle with at least one chemically reactive portion as a linker, and the association of at least one linker with at least one trapping agent (specifically sulfonic acid) and its derivatives or the like, such that the linker is positioned between the particle and the trapping agent, its derivatives or the like, thus associating with the particle at one end (on one arm) and with the trapping agent, its derivatives or the like at the other end (on a second different arm).

[0472] In some embodiments, the trapping agent (specifically a sulfonic acid) and its derivatives bind specifically and selectively to a particular target, in this case at least one amine (e.g., ammonia), and are capable of effectively trapping, immobilizing, distributing, and removing ammonia from liquid substances (specifically body fluids).

[0473] As used herein, the term “association” or any linguistic variant thereof refers to a chemical or physical force that holds two entities (e.g., particles and connecting groups) together. Such a force can be any type of chemical or physical bonding interaction known to those skilled in the art.

[0474] Non-limiting examples of such associative interactions include covalent bonding, ionic bonding, coordination bonding, complexation, hydrogen bonding, van der Waals bonding, hydrophobic-hydrophilic interactions, etc. Therefore, the association / conjugation of the linker to at least one particle and the association / conjugation of the linker to the trapping agent can be achieved via any chemical bonding, including covalent bonding, electrostatic interactions, acid-base interactions, van der Waals interactions, etc. As understood, the association of the particle to the linker and the association of the linker to the trapping agent, its derivatives, or analogues can be the same or different, as further detailed below.

[0475] The particles of the present invention may include any polymer particles capable of incorporating the linker of the present invention.

[0476] In some implementations, the particles are resin beads.

[0477] As used herein, the term "particle" refers to a substance whose surface can be attached to a chemical or biological compound, a macromolecule, or a portion thereof, via covalent or non-covalent bonding. Particles may comprise porous materials. Particles may be, for example, "spherical" (generally referring to a geometry that is substantially (almost) spherical) or "non-spherical" (having a "long and thin" shape with defined long and short axes). Non-limiting examples of particles include beads, such as at least one of the following: polysaccharide beads, glass beads, cotton beads, plastic beads, nylon beads, latex beads, magnetic beads, paramagnetic beads, superparamagnetic beads, starch beads, etc., silicon beads, PTFE beads, polystyrene beads, gallium arsenide beads, gold beads, or silver beads. In some embodiments, particles are beads including agarose beads, optionally having different degrees of crosslinking at different material (agarose) % percentages.

[0478] Therefore, agarose beads encompass beads containing agarose with varying degrees of cross-linking, such as beads called Sepharose beads. In some embodiments, the beads comprise agarose beads. In some embodiments, the beads comprise Sepharose beads. In some embodiments, the multiple conjugates comprise a combination of particles containing both agarose beads and Sepharose beads. According to this disclosure, it should be noted that particles containing either agarose beads or Sepharose beads are considered as two different conjugates with different particle sizes.

[0479] As described herein, particles, specifically beads, can associate with a chemically reactive portion (referred to herein as a linker). The linker, as used herein, can be any chemical entity composed of any combination of atoms, including oligomer chains and polymer chains of any length, and according to some embodiments, the linker is capable of binding to one end of the particle and to at least one trapping agent, its derivative, or the like at the other end.

[0480] In some embodiments, the beads can associate with a linker via a spacer group or coating present on the beads. Thus, the beads are initially activated by association with the spacer group / coating (“activated beads”) and then react with the linker group. It should be noted that sometimes, in cases where the spacer group / coating is directly bound to at least one trapping agent, a linker group may not be necessary. Sometimes, the beads lack functional groups capable of binding to the linker group, and therefore a spacer group or coating can be used.

[0481] Activated beads are obtained by pre-coating the beads with a suitable material having an active portion that enables binding to the beads as well as to linkers and / or traps. In other words, the beads are pre-coated to include reactive groups that enable covalent bonding to linkers or traps.

[0482] In some embodiments, the beads can be activated, for example, by pre-coating with any coating material. Non-limiting examples of such materials include, for example, amino acids, proteins, epoxy resins, toluenesulfonyl groups, carboxylic acids, and carboxylated polyvinyl alcohol. When referred to as "pre-coating," it should be understood as a preliminary step of coating the beads with an active material that enables the beads to covalently bind with sulfonic acids (i.e., directly) or via at least one linker. In some embodiments, the beads are pre-coated with amino acids, peptides, or any derivatives thereof. Pre-coated magnetic beads may contain, for example, primary amines (–NH2), carboxyl groups (–COOH), thiol groups (–SH), or carbonyl groups (-CHO) as active groups. In some embodiments, the beads are pre-coated to include a portion that can react with primary or secondary amino groups. In some other embodiments, the magnetic beads are coated with polylysine.

[0483] As used herein, the term “connecting base” encompasses any spacer base or pre-coating present on the beads.

[0484] In some embodiments, the linker is or comprises an atomic chain, such as a straight chain. In some embodiments, the linker comprises at least 1 atom, at least 4 atoms, sometimes 5 atoms, sometimes 10 atoms, sometimes 20 atoms, sometimes 30 atoms, and sometimes 40 atoms. In some embodiments, the linker is or comprises a straight chain of 1 to 40 atoms. In some embodiments, the linker is or comprises a straight chain of 1 atom. In some embodiments, the linker is a straight chain comprising 5 atoms. In some embodiments, the linker is a straight chain comprising 15 atoms.

[0485] In some embodiments, the particles are resin beads. In some embodiments, the particles may be agarose beads; therefore, in some embodiments, the resin beads are agarose resin, which may contain between about 2% and 10% agarose. Further, in some embodiments, the resin beads may contain between 3% and 9% agarose, and even further, in some embodiments, the resin beads may contain between 4% and 8% agarose. In some embodiments, the resin beads contain at least 4% agarose.

[0486] In some other implementations, the amount of agarose in the granules is at least 5%, and sometimes at least 6%.

[0487] In some embodiments, the conjugates of this disclosure comprise particles with an average particle size between about 10 µm and about 500 µm. Specifically, particles with a particle size 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 larger. In some specific embodiments, the multiple conjugates comprise particles with 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 between about 40 µm and about 170 µm.

[0488] The terms "average size," "average diameter," or "mean size" refer to the arithmetic mean of measured diameters, where the diameter is within ±25% of this average. The mean size of the particles can be measured by any method known in the art. In some embodiments, the size of the resin beads is between 40 µm and 170 µm, where the average size is between 80 µm and 100 µm. Sometimes, the average size is 90 µm.

[0489] In some embodiments, the various conjugates according to this disclosure may be particularly suitable for depleting at least one amine from at least one liquid substance.

[0490] In some other embodiments, the trapping agent A of the various conjugates according to this disclosure is specifically configured to capture at least one amine. In some embodiments, the amine is ammonia. In some other embodiments, the liquid substance is a mammalian body fluid. Therefore, in some embodiments, the various conjugates provided by this disclosure are particularly suitable for depleting ammonia from a mammalian body fluid.

[0491] In some embodiments, the various conjugates according to this disclosure may be particularly suitable for depleting at least one amine from at least one liquid substance.

[0492] Another aspect of this disclosure relates to multiple conjugates, or any composition comprising multiple conjugates. In a more specific embodiment, each conjugate comprises particles, at least one linker, and at least one trapping agent A, or any derivative or analog thereof. More specifically, the conjugates of this disclosure comprise particles bonded to at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group;

[0493]

[0494] Formula I

[0495] Where 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 trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0496] In some embodiments, the various conjugates disclosed in this invention, or conjugates in any composition, are as defined in this disclosure.

[0497] In some embodiments, the various conjugates according to this disclosure may be particularly suitable for depleting at least one amine from at least one liquid substance.

[0498] In some other embodiments, the trapping agent A of the various conjugates according to this disclosure is specifically configured to capture at least one amine. In some embodiments, the amine is ammonia. In some other embodiments, the liquid substance is a mammalian body fluid. Therefore, in some embodiments, the various conjugates provided by this disclosure are particularly suitable for depleting ammonia from a mammalian body fluid.

[0499] Another aspect of this disclosure relates to a method for depleting at least one amine from a liquid substance. More specifically, the method includes the following steps:

[0500] In the first step (i), the liquid substance is subjected to an affinity depletion process specifically for the at least one amine. The next step (ii) involves recovering the at least one amine-depleted liquid obtained in step (i). In some embodiments, the affinity depletion process includes contacting the liquid substance with an effective amount of at least one conjugate, multiple conjugates, or a composition containing the conjugate or multiple conjugates, or applying the liquid substance to a device, battery, or external device containing a conjugate of the present disclosure. In a more specific embodiment, each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0501]

[0502] Formula I

[0503] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0504] It should be understood that, in some embodiments, the conjugates of this disclosure may comprise any combination of any number (m) of carbonyl groups and any number (n) of straight-chain alkanes. Therefore, in some embodiments, the various conjugates discussed herein may comprise any mixture or combination of any conjugates combining 5 to 15 straight-chain alkanes (n) with 5 to 10 carbonyl groups.

[0505] In some embodiments, the liquid substance used in the methods disclosed herein is mammalian body fluid or any product thereof.

[0506] In some other 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 this disclosure is used to deplete ammonia from the body fluids of mammals. As noted above, the method of this disclosure is suitable for depleting and reducing ammonia from at least about 0.5 liters to about 10 liters of body fluid (specifically, between about 2 liters and 3 liters of body fluid).

[0507] It should be noted that in some embodiments, any of the conjugates, multiple conjugates or compositions, devices and / or batteries used by the methods discussed herein are as defined in this invention.

[0508] As noted above, the method of the present invention relates to an extracorporeal procedure. In some embodiments, the extracorporeal device is a cardiopulmonary bypass machine (CPB), and in some embodiments, the extracorporeal device is a plasma exchange machine.

[0509] The term "extracorporeal" refers to medical procedures performed outside the body. For example, such extracorporeal procedures can involve circulatory processes, which involve drawing blood from a patient's circulation to treat it before it is returned to the circulation. All devices that transport blood outside the body are called extracorporeal circuits. Such circulatory processes include, but are not limited to: apheresis, autologous blood transfusion, hemodialysis, hemofiltration, plasma exchange, extracorporeal carbon dioxide removal, extracorporeal cardiopulmonary resuscitation, extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass during open-heart surgery.

[0510] 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 heart-lung machine or simply a "pump." The CPB pump is operated by a perfusionist. CPB is a form of extracorporeal circulation. Extracorporeal membrane oxygenation (ECMO) is typically used for long-term treatment.

[0511] Apheresis is a device that takes blood from a subject in need and separates it into various components, including plasma, platelets, white blood cells, and red blood cells.

[0512] Another aspect of the invention relates to a method for depleting at least one amine from the bodily fluids of a subject in need. More specifically, the method may include contacting the bodily fluids with an effective amount of the conjugate, multiple conjugates, or a combination thereof, or within a device or battery containing the conjugate, or alternatively, with an in vitro device containing the conjugate or device described herein or connected to the conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0513]

[0514] Formula I

[0515] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step involves recovering the amine-free bodily fluid and, optionally, reintroducing the bodily fluid into the subject in need.

[0516] In some other specific and non-limiting embodiments, the method may include the use of an external procedure. More specifically, the method may include the following steps:

[0517] First, in step (i), the subject's bodily fluids are transferred to an external device.

[0518] The next step (ii) involves subjecting the body fluid to an affinity depletion procedure dedicated to at least one amine, wherein the depletion is performed before, during, or after the transfer of blood into and from the device, thereby obtaining the subject's in vitro body fluid depleted of at least one amine.

[0519] The next step (iii) involves reintroducing or returning the bodily fluid obtained in step (ii) to the subject. As noted above, the affinity depletion procedure involves contacting the subject's bodily fluid with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or within a device or battery connected to the external device. Each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0520]

[0521] Formula I

[0522] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0523] In some embodiments, the conjugates, multiple conjugates or compositions, devices, batteries and equipment used in the methods of the present invention are any of those disclosed in this disclosure.

[0524] In some embodiments, the conjugate used in the method of this disclosure has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0525]

[0526] Formula V

[0527] Where m is an integer between 5 and 10.

[0528] In some embodiments, the methods disclosed in this invention can be applied to deplete ammonia from any liquid material or substance, particularly from bodily fluids. As used herein, bodily fluids or biological fluids are fluids within the bodies of mammals, particularly humans. The term may refer to any bodily fluid in some embodiments, including blood, plasma, saliva, vaginal secretions, semen, urine, mucosal fluids, etc., but in the context of this disclosure, it refers to blood and plasma as discussed below. The average total body water volume is about 60% (60% to 67%) of total body weight; typically slightly lower in women (52% to 55%). The precise percentage of fluid relative to body weight is inversely proportional to the percentage of body fat. The total body water volume is divided into multiple fluid compartments, with a ratio of 2:1 between intracellular fluid (ICF) compartments (also called spaces or volumes) and extracellular fluid (ECF) compartments (spaces, volumes): 28 (28–32) liters intracellularly and 14 (14–15) liters extracellularly. The ECF compartment is divided into interstitial fluid volume (i.e., fluid outside both cells and blood vessels) and vascular volume (also known as vascular volume and plasma volume, i.e. fluid inside blood vessels), with a ratio of three to one: the interstitial fluid volume is about 12 liters and the vascular volume is about 4 liters.

[0529] In some implementations, the body fluid referred to herein is plasma. Plasma is the liquid component of blood that does not contain blood cells but holds proteins and other components of the whole blood in suspension. Plasma constitutes approximately 55% of the total blood volume. As discussed above, plasma is the intravascular portion of the extracellular fluid. Plasma is primarily composed of water (up to 95% by volume), containing important lysed proteins (6% to 8%) (e.g., serum albumin, globulins, and fibrinogen), glucose, clotting factors, and electrolytes (Na+, Na+, and Na+). + Ca 2+ Mg 2+ HCO3 Cl (etc.), hormones, carbon dioxide, and oxygen. The density of plasma is approximately 1025 kg / m³. 3Or 1.025 g / ml. Furthermore, in some embodiments, the bodily fluids that can be used in this disclosure may be serum, i.e., plasma free of clotting factors as discussed herein.

[0530] In some embodiments, the methods disclosed in this invention can be applied to deplete ammonia from body fluids, wherein the body fluids may be at least one of whole blood, plasma, or blood-derived products.

[0531] In some specific implementations, such blood-derived products may be at least one of whole blood, plasma, fresh frozen plasma (FFP), platelet-rich plasma (PRP), and frozen proteins.

[0532] It should be understood that, in some embodiments, the methods disclosed in this invention can be performed outside the body or in vitro. More specifically, they can be performed in bodily fluids that are no longer part of the human body.

[0533] This disclosure provides conjugates, apparatus, and methods for depleting ammonia from bodily fluids to obtain ammonia-reduced, ammonia-depleted bodily fluids. As used herein, "ammonia-depleted or reduced bodily fluids" or "ammonia-free bodily fluids" means that the products of the subject matter of this invention (which, according to some embodiments, have been prepared by treating bodily fluids (such as blood, plasma, or blood products) with an ammonia binder, particularly the apparatus and conjugates disclosed herein) exhibit a reduction, decrease, or attenuation of ammonia by about 50% to 100% compared to untreated blood or blood products. More specifically, prior to depletion using the methods, apparatus, and conjugates disclosed herein, 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 bodily fluids (specifically, blood or blood products) is removed from the products of the subject matter of this invention, particularly compared to untreated blood or blood products. In other words, the ammonia content in the products disclosed in this invention can be from about 0.01% to about 50% of the ammonia content in other products or untreated blood or blood products (especially blood, plasma, or blood products not treated by the conjugates, apparatus, and methods of this disclosure). Specifically, compared to untreated blood or blood products, the ammonia content is less than about 0.01%, and less than 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%, or 70%.

[0534] As noted above, bodily fluids, blood, plasma, or blood products treated by the methods disclosed in this invention show a reduction, decrease, or depletion of ammonia levels. It should be understood that the terms "reduction" or "depletion" as used herein refer to a reduction or decrease in the amount of at least one amine (specifically, ammonia) by any percentage in the range of about 1% to 99.9% compared to the following: specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 6 0% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85%, about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%, or even 100%: bodily fluids containing ammonia (such as blood, plasma, or blood products), blood or blood products not treated with conjugates disclosed in this invention, blood of a subject suffering from a condition associated with elevated ammonia levels, and in some embodiments, normal blood or blood products, or commercially available blood products. In other words, these products show no ammonia, or at most show the minimum and reduced amount of ammonia, compared to the ammonia content of untreated blood, plasma, or blood products or any other bodily fluids; specifically, ammonia levels of less than about 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%, or 50%. In some embodiments, bodily fluids, blood, plasma, or blood products treated by the methods, conjugates, compositions, and devices, batteries, kits, or systems provided by the subject matter of this invention show a reduction or absence of ammonia as defined above and can be used for any therapeutic application disclosed in the subject matter of this invention, as discussed below.

[0535] In some other specific embodiments, the method of the subject matter disclosed in this invention can be used in vivo / in vitro to deplete at least one ammonia from the bodily fluids of a subject in need and / or in a subject in need.

[0536] Another aspect of this disclosure relates to a method for treating, preventing, ameliorating, or inhibiting conditions or pathological conditions associated with elevated blood ammonia levels in a subject by depleting ammonia from the body fluids of the subject in need.

[0537] More specifically, the treatment methods disclosed herein may include contacting the bodily fluids of a treated subject with an effective amount of the conjugate, multiple conjugates, or a combination thereof, or within a device or battery containing the conjugate, or alternatively, with an external device containing the conjugate and / or device described herein, or connected to the conjugate or device disclosed herein. It should be noted that each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0538]

[0539] Formula I

[0540] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine. The next step involves recovering the amine-free bodily fluid and optionally reintroducing the bodily fluid into the treated subject.

[0541] In some other specific and non-limiting embodiments, these methods may include the use of an external procedure. More specifically, the method may include the following steps:

[0542] First, in step (i), the subject's bodily fluids are transferred to an external device.

[0543] The next step (ii) involves subjecting the body fluid to an affinity depletion procedure dedicated to at least one amine, wherein the depletion is performed before, during, or after the transfer of blood into and from the device, thereby obtaining an in vitro body fluid of the treated subject depleted of at least one amine.

[0544] The next step (iii) involves reintroducing or returning the bodily fluid obtained in step (ii) to the subject. As noted above, the affinity depletion procedure involves contacting the subject's bodily fluid with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or within a device or battery connected to the external device. Each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group.

[0545]

[0546] Formula I

[0547] Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines. Optionally, the amine is at least one of methylamine, dimethylamine, or trimethylamine.

[0548] In some embodiments, the conjugates, multiple conjugates or compositions, devices, batteries and apparatus used in the treatment methods of the present invention are any of those disclosed in this disclosure.

[0549] In some embodiments, the conjugate used in the treatment methods of this disclosure has structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group.

[0550]

[0551] Formula V

[0552] Where m is an integer between 5 and 10.

[0553] In some embodiments, the methods, systems, apparatus, devices, and conjugates of this disclosure may be applicable to any condition associated with elevated blood ammonia levels, including chronic or acute liver and / or chronic or acute lung conditions, cognitive decline, any other condition associated with neuronal and / or nerve damage, and hyperammonemia and related conditions.

[0554] In some specific implementations, liver condition refers to hepatic encephalopathy and any related conditions. Hepatic encephalopathy is a decline in brain function that occurs due to severe liver disease. In this condition, the liver is unable to adequately remove toxins from the subject's blood. This causes toxins to accumulate in the bloodstream, potentially leading to brain damage.

[0555] Hepatic encephalopathy can be acute (short-term) or chronic (long-term). In some cases, people with hepatic encephalopathy may become unresponsive and fall into a coma.

[0556] Acute hepatic encephalopathy can also be a sign of late-stage liver failure. Chronic hepatic encephalopathy can be permanent or recurrent.

[0557] Furthermore, hepatic encephalopathy is a syndrome commonly observed in patients with cirrhosis. Hepatic encephalopathy is defined as a series of neuropsychiatric abnormalities in patients with abnormal liver function after excluding brain diseases. Hepatic encephalopathy is characterized by personality changes, intellectual impairment, and decreased level of consciousness. A key prerequisite for this syndrome is the shunting of portal blood into the systemic circulation via collateral vessels of the portal venous system. Hepatic encephalopathy is also described in patients with spontaneous or surgically induced portosystemic shunting but without cirrhosis. The development of hepatic encephalopathy is partly explained by the effects of neurotoxic substances occurring in the context of cirrhosis and portal hypertension.

[0558] In some embodiments, the methods, systems, apparatus, devices, and conjugates of this disclosure can be adapted to any condition, symptom, or ailment associated with hyperammonemia. As used herein, hyperammonemia is the pathological accumulation of ammonia in the blood, which can occur in many different clinical settings. In adults, hyperammonemia is most commonly secondary to liver dysfunction; however, it is also known to be associated with other conditions, surgeries, and pharmacological treatments. Although less common, hyperammonemia has been described as a rare but consistent complication of solid organ transplantation. Lung transplantation is increasingly recognized as a unique risk factor for the development of this condition, which can pose serious health risks, including long-term neurological sequelae and even death. A wide variety of etiologies are attributed to this condition. A growing number of case studies and investigations suggest that diffuse opportunistic infections of species of Ureaplasma or Mycoplasma may drive this metabolic disorder in lung transplant recipients. Regardless of the etiology, hyperammonemia presents serious clinical problems, with reported mortality rates as high as 75%. Surviving patients often suffer from significant long-term neurological sequelae, such as cognitive impairment. Therefore, it should be understood that the methods, systems, apparatuses, devices, and conjugates disclosed herein are applicable to the treatment and prevention of hyperammonemia, particularly hyperammonemia following solid organ transplantation. In some embodiments, the methods, systems, apparatuses, devices, and conjugates disclosed herein are applicable to patients undergoing lung transplantation.

[0559] Furthermore, ammonia (NH3) is a common metabolite in the human body, but supraphysiological levels in the systemic circulation can lead to severe neurological damage and even death.

[0560] In children, ammonia is typically associated with congenital metabolic errors involving urea cycle enzymes and transport proteins (collectively, urea cycle disorders (UCD)). Therefore, it should be understood that in some embodiments, the methods, systems, devices, apparatuses, and conjugates of this disclosure may be suitable for treating and / or improving UCD.

[0561] Furthermore, in some embodiments, the methods, systems, apparatus, devices, and conjugates of this disclosure may be applicable to chronic kidney disease, hemorrhagic shock, and any hyperammonemia-related conditions well understood and reported in the literature.

[0562] 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 systemic circulation, NH3 can cross the blood-brain barrier through multiple mechanisms, including gas diffusion, passive diffusion in its soluble form through membrane channels, and competitive diffusion through potassium channels. In the brain, NH3 is taken up by astrocytes and converted to glutamine by glutamine synthase (GS). This leads to a series of adverse events. Significantly elevated glutamate increases osmotic pressure, causing aquaporin rupture, ultimately leading to cerebral edema and hypertension characteristic of hyperammonemia. Accompanying this is the release of various pro-inflammatory cytokines from astrocytes, such as tissue necrosis factor-α (TNF-α). Astrocyte damage and subsequent downregulation of their glutamate receptors can trigger excessive glutamatergic activity in adjacent synapses, resulting in excitotoxicity, which leads to encephalopathy and seizures commonly seen in hyperammonemia.

[0563] Similar physiological changes associated with increased GABAergic tonicity occur in Purkinje cells of the cerebellum, which may explain the ataxia and myoclonus also observed in this metabolic disorder. Delay in recognition and appropriate management can lead to significant long-term morbidity, including refractory status epilepticus, motor and cognitive impairment, cerebral palsy, and death. Therefore, in some embodiments, the methods, systems, devices, apparatuses, and conjugates of this disclosure are applicable to any neuronal condition disclosed herein, and any related conditions. For example, in adults, such conditions can be further characterized as altered mental status, somnolence, mood and personality disorders, ataxia, vomiting, seizures, unconsciousness, and possible death.

[0564] As noted above, the subject matter disclosed in this invention provides methods for treating conditions associated with elevated ammonia levels and any conditions associated with such conditions. As used herein, the terms “disease,” “symptom,” “condition,” etc., are used interchangeably when referring to the health status of the subject and have the meaning belonging to each and all such terms.

[0565] It should be understood that when referring to symptoms in this document, the terms “associated” and “related” are used interchangeably to mean a disease, symptom, condition or any symptom that has at least one of the following characteristics: a shared causal relationship, coexistence at a frequency higher than coincidence, or at least one of the diseases, symptoms, conditions or symptoms causing a second disease, symptom, condition or symptom.

[0566] As mentioned above, the subject matter disclosed in this invention provides a method for treating the conditions specified above. As used herein, the term "treatment" refers to the application of a therapeutic amount of the composition of the subject matter disclosed in this invention, which is capable of effectively improving undesirable symptoms associated with the disease, preventing the onset of such symptoms before they appear, slowing disease progression, slowing symptom exacerbation, enhancing the onset of remission, slowing irreversible damage caused in the progressive chronic phase of the disease, delaying the onset of said progressive phase, reducing the severity of the disease or curing the disease, improving survival or faster recovery, preventing the occurrence of the disease, or a combination of both or more of the above. Treatment may be initiated at the initial development of a hemostatic condition, or may be applied continuously, for example, daily, every 1 to 7 days, every 7 to 15 days, every 15 to 30 days, every month to every two months, every two months to every six months, or even longer, more than once, to achieve the therapeutic effects listed above.

[0567] The term "prevention" refers to preventing or reducing the risk of biological or medical events, specifically the prevention of the occurrence or recurrence of conditions associated with elevated ammonia levels in tissues, systems, animals, or humans, sought by researchers, veterinarians, physicians, or other clinicians. The term "preventatively effective amount" is intended to represent the amount of pharmaceutical composition that will achieve this objective. Therefore, in certain embodiments, the methods of the subject matter disclosed in this invention are particularly effective in prevention (i.e., prevention of conditions associated with elevated ammonia levels). Consequently, subjects administering the composition are less likely to experience symptoms associated with the elevated ammonia levels, and the elevated ammonia levels are less likely to recur in subjects who have previously experienced these conditions.

[0568] As mentioned herein, the term "improvement" refers to a reduction in symptoms and a better condition of a subject caused by the compositions and methods disclosed in this invention, wherein said improvement may take the form of: inhibiting pathological processes associated with symptoms of elevated ammonia levels as described herein, significantly reducing their severity, or improving the physiological state of the affected subject.

[0569] The term “inhibition” and all variations thereof are intended to cover the restriction or prohibition of the progression and worsening of pathological symptoms, or the progression of pathological processes associated with the symptoms or progression of the pathological process.

[0570] The term “elimination” refers to the method, optionally according to the subject matter of the invention disclosed below, which substantially eradicates or removes pathological symptoms and possible pathological causes.

[0571] The terms “delay,” “delayed onset,” “slowing down,” and all variations thereof are intended to cover slowing the progression and / or worsening of conditions and symptoms associated with elevated ammonia levels, so as to occur later than in the absence of a treatment according to the subject matter disclosed in this invention.

[0572] As mentioned above, treatment or prevention includes preventing or delaying the progression of the disease, preventing or delaying the development of symptoms, and / or reducing the severity of such symptoms that are about to develop or are expected to develop. This also includes improving existing symptoms, preventing additional symptoms, and improving or preventing the underlying metabolic causes of symptoms. It should be understood that the terms “suppression,” “mitigation,” “reduction,” or “attenuation” as used herein refer to delaying, limiting, or reducing the progression (specifically, the condition associated with elevated ammonia levels) by any percentage in the range of approximately 1% to 99.9%, specifically, approximately 1% to approximately 5%, approximately 5% to 10%, approximately 10% to 15%, approximately 15% to 20%, approximately 20% to 25%, approximately 25% to 30%, approximately 30% to 35%, approximately 35% to 40%, approximately 40% to 45%, approximately 45% to 50%, approximately 50% to 55%, approximately 55% to 60%, approximately 60% to 65%, approximately 65% ​​to 70%, approximately 75% to 80%, approximately 80% to 85%, approximately 85% to 90%, approximately 90% to 95%, approximately 95% to 99%, or approximately 99% to 99.9%.

[0573] Single or multiple administration regimens, whether daily, weekly, or monthly, can be administered according to the dosage level and pattern chosen by the treating physician. More specific implementation plans involve typically using 2 to 3 doses per week.

[0574] The subject matter disclosed in this invention relates to treating subjects or patients in need of such treatment. The term "patient" or "subject in need" means any organism that may be infected by the pathogens mentioned above, and any organism that requires the preventative and protective products, kits, and methods described herein, including humans, domestic and non-domestic mammals (such as canine and feline subjects, cattle, apes, horses, and rodent subjects), rodents, poultry, aquaculture, fish, and exotic ornamental fish. It should be understood that subjects receiving treatment can also be any reptile or zoo animal.

[0575] The term "mammal subject" refers to any mammal requiring the proposed therapy, including humans, equines, canines, and felines, with a particular emphasis on humans. It should be noted that, specifically in the case of non-human subjects, the methods disclosed in this invention can be administered directly into the digestive tract of the subject in need via injection (intravenous (IV), intra-arterial (IA), intramuscular (IM), or subcutaneous (SC)), drinking water, feed, spray, or oral lavage solution.

[0576] The methods discussed herein refer to the use of an effective amount. It should be understood that the terms "effective amount" or "sufficient amount" as used in the methods of this invention 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 eliminate and / or reduce the level of at least one amine in bodily fluids, specifically, to deplete ammonia or at least reduce ammonia levels in bodily fluids. Furthermore, such an effective amount is sufficient to provide bodily fluids containing normal and / or non-toxic levels of ammonia. As used herein, an "effective therapeutic amount" is determined by the severity of the disease in combination with preventative or therapeutic purposes, the route of administration, and the patient's general condition (age, sex, weight, and other considerations known to the attending physician). In the context of this invention, an "effective therapeutic amount" means an effective amount of the conjugates of this invention used by the devices, systems, apparatus, and methods disclosed herein, which is necessary to deplete and / or eliminate and / or reduce ammonia levels in bodily fluids to treat, prevent, avoid, and improve any condition associated with elevated ammonia levels as discussed above.

[0577] Unless otherwise specified, all scientific and technical terms used herein have their common meaning in the art. The definitions provided herein are for the purpose of understanding certain terms used frequently herein and are not intended to limit the scope of this disclosure.

[0578] All definitions defined and used herein should be understood to take precedence over dictionary definitions, definitions in referenced documents, and / or the general meaning of the defined terms.

[0579] As used herein, the term “about” means a value that may deviate from the mentioned value by up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20%, including integer values ​​that constitute a continuous range, and, where applicable, non-integer values. As used herein, the term “about” means ±10%.

[0580] Unless explicitly indicated otherwise, the indefinite articles “a” and “an” as used herein in the specification and claims shall be understood to mean “at least one / a kind”. It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise.

[0581] The phrase “and / or” as used herein in the specification and claims should be understood to mean “any one or both” of the elements so combined (i.e., elements that exist in combination in some cases and separately in others). Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so combined. Other elements may optionally exist that are different from those specifically indicated by the “and / or” clause, whether or not they are related to those specifically indicated elements. Thus, as a non-limiting example, in one embodiment, when used in conjunction with open-ended language such as “comprising,” reference to “A and / or B” may refer only to A (optionally including elements different from B); in another embodiment, only to B (optionally including elements different from A); in yet another embodiment, to both A and B (optionally including other elements); and so on.

[0582] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, that is, including multiple elements or at least one element in the list of elements, but also including more than one element therein, and optionally including additional unlisted items. Only when the term clearly indicates the opposite meaning, such as “only one of…” or “only one of…”, or when used in the claims, “consisting of…” will it refer to including multiple elements or only one element in the list of elements. Generally speaking, when the term “or” as used herein is used in the claims, when followed by exclusive terms such as “any one of…”, “one of…”, “only one of…”, or “only one of…”, it should be interpreted only as indicating an exclusive alternative (i.e., “one or the other, but not both”). “Substantially consisting of…” when used in the claims should have its ordinary meaning as used in the field of patent law.

[0583] As used herein in the specification and claims, the phrase “at least one” in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list, but not necessarily including at least one of every element specifically listed in the list, nor excluding any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically specified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically specified elements. Thus, as a non-limiting example, in one embodiment, “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 at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, it refers to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, it refers to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0584] It should also be understood that, unless clearly indicated to the contrary, in any method that claims rights herein and includes more than one step or action, 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 recorded.

[0585] Throughout this specification and the following embodiments and claims, unless the context otherwise requires, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “constituting,” etc., shall be understood as open-ended, i.e., meaning including but not limited to. Only the transitional phrases “constituting of” and “substantially consisting of” shall be closed or semi-closed transitional phrases as presented in the U.S. Patent Examination Procedure Manual. More specifically, the terms “comprising,” “containing,” “including,” “having,” and their inflections all mean “including but not limited to.” The term “constituting of” means “including and limited to.” The term “substantially consisting of” means that a composition, method, or structure may include additional ingredients, steps, and / or portions, but only when such additional ingredients, steps, and / or portions do not substantially alter the essential and novel features of the claimed composition, method, or structure.

[0586] It should be noted that various embodiments of the subject matter disclosed in this invention can be presented in a range format. It should be understood that the range format is merely for convenience and brevity and should not be construed as imposing a rigid limitation on the scope of the subject matter disclosed in this invention. Therefore, a description of a range should be considered as specifically disclosing all possible subranges, and the individual numerical values ​​within that range. For example, a description of a range such as from 1 to 6 should be considered as specifically disclosing subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range. Whenever a range of numerical values ​​is indicated herein, it is intended to include any referenced number (fractional or integer) within the indicated range. The quotation marks “range between the first and second indicated numbers” and “range from the first indicated number to the second indicated number” are used interchangeably herein and are intended to include the first and second indicated numbers, and all fractional and integer numbers between them.

[0587] As used herein, the term "method" refers to the manner, means, techniques, and procedures used to accomplish a given task, including but not limited to those manner, means, techniques, and procedures known to or readily developed by practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0588] It should be understood that certain features of the subject matter disclosed in this invention, described for clarity in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the subject matter disclosed in this invention, described for simplicity in the context of a single embodiment, may also be provided individually or in any suitable sub-combination, or, where appropriate, in any other described embodiment of the subject matter disclosed in this invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments unless the embodiment cannot be implemented without those elements.

[0589] Various embodiments and aspects of the subject matter disclosed in this invention as described above and claimed in the claims section below are experimentally supported in the following examples.

[0590] It should be understood that the subject matter disclosed herein is not limited to the specific embodiments, method steps, and compositions disclosed herein, as such method steps and compositions can be modified slightly. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the subject matter disclosed herein will be limited only by the appended claims and their equivalents.

[0591] The following examples illustrate techniques employed by the inventors in carrying out various aspects of the subject matter disclosed herein. It should be understood that while these techniques are examples of preferred embodiments for practicing the subject matter disclosed herein, those skilled in the art will recognize, based on this disclosure, that many modifications can be made without departing from the spirit and scope of the subject matter disclosed herein.

[0592] Example

[0593] Experimental Procedure

[0594] Preparation of linker for coupling 4% agarose beads

[0595] Resin active groups: -COOH groups

[0596] • Group to be coupled: -NH2 group

[0597] • Particle size range 45µm to 165µm, average 90µm

[0598] • Spherical cross-linked agarose

[0599] • Coupling conditions: 4°C to 25°C, pH: 4.5 to 6, maintenance time: 1.5 to 24 hours. Coupling can be carried out in organic solvents.

[0600] • No capping reaction is required after the coupling reaction.

[0601] • Storage temperature: 2℃ to 8℃

[0602] plan :

[0603] Dissolve the linker to be coupled in a coupling solution at pH 4.5 to 6.

[0604] Preparation of resins for coupling ligands

[0605] Wash an appropriate amount of resin five times with distilled water (pH 4.5 to 6).

[0606] 1. Add the linker solution to the agarose beads at a ratio of 1:0.5 to 1:1, mix gently, and prepare a suspension.

[0607] 2. Add the carbodiimide solution to the suspension to a final concentration of 0.1 M.

[0608] 3. Rotate the suspension upside down for 4 hours at 4°C to RT.

[0609] 4. During the first hour of the reaction, adjust the pH of the reaction mixture with 0.1M NaOH.

[0610] 5. Wash the resin with 0.1M acetate buffer (pH 4) containing 0.5M NaCl, followed by washing with 0.1M Tris-HCl buffer (pH 8) containing 0.5M NaCl.

[0611] 6. Repeat step 5 twice.

[0612] 7. If no organic solvent is used in the coupling, rinse the resin with 5 to 10 times its volume of distilled water.

[0613] 8. Following this, sulfenic acid will be added according to steps 1 to 7.

[0614] Measuring ammonia in plasma

[0615] To deplete ammonia from plasma, the plasma and resin should be shaken and incubated at a 1:10 ratio for 1 hour. During incubation, ammonia particles collide and are specifically captured by the resin. The efficacy of the incubation process is checked by measuring the ammonia concentration and depletion percentage in control plasma and incubated plasma: 100 – (concentration of incubated plasma / concentration of control plasma).

[0616] Ammonia concentration can be detected using an ammonia assay kit (catalog number: KA0810, manufacturer: Abnova). Ammonia or ammonium is converted into a product that reacts with an OxiRed probe to produce a color (OD 570 nm), which can be easily quantified using a plate reader. This kit can detect 1 nmol (approximately 20 µM) of ammonia or ammonium.

[0617] Establishing a porcine model of acute liver failure

[0618] A midline incision is made from the xiphoid process to the pubis. The portal vein is incised from the hepatic hilum to the confluence of the splenic veins, and surrounding tissues and lymph nodes are removed. The inferior vena cava adjacent to the head of the renal vein is removed and clamped with a dissecting clip, and a 1.5 cm longitudinal incision is made. Then, the portal vein is clamped, displaced, and anastomosed to the inferior vena cava using continuous "over-and-over" polypropylene 5-0 sutures. The total time for portal vein occlusion is 11 to 15 minutes. During this period and for an additional 10 minutes, 1000 ml of 0.9% NaCl is infused into each animal to maintain arterial pressure. The structures in the hepatoduodenal ligament are carefully dissected to ensure that the arterial blood supply to the liver is also completely interrupted. At the end of the experiment, the animals are euthanized.

[0619] Example 1

[0620] Synthetic conjugates and assembly devices

[0621] The conjugate comprising agarose beads, a linker, and sulfuric acid was prepared as shown in the experimental procedure. More specifically, 6% agarose beads were linked to a linker having 15 carbon atoms and sulfonic acid. Figure 15 A schematic diagram of the conjugate is shown. Based on Figure 17B The standard curve shown is used to calculate the amount of ammonia in body fluids.

[0622] Figure 1 A non-limiting example of a filtration device comprising the conjugate of the present invention is shown, used in conjunction with a blood component apheresis unit to absorb ammonia from the blood system. The filter comprises a resin with chemically bonded groups, a housing (plastic), and a universal connecting tube for connecting the filter to the blood component apheresis unit.

[0623] Example 2

[0624] Depletion of ammonium from pig body fluids

[0625] Preclinical studies were conducted in Phase I. Animal studies were conducted using pigs. Pigs were housed in an animal facility for at least two days prior to the experiment. Conditions in the animal facility were controlled (21°C, 30%–40% relative humidity, 12-hour:12-hour light-dark cycle). Animals were fed regularly. After two days, all animals were fasted overnight with free access to water. Veterinary care services were provided to the animals, with continuous monitoring of their general health status prior to the experiment. Acute liver failure (ALF) induced by ammonia elevation was induced using a distal portacaval shunt, followed by ligation of the hepatic artery. All animals were administered saline, glucose, and albumin IV as described in the experimental procedure. Ammonia levels were monitored once ALF was induced. Figure 17A An example of the pigs used in this study is shown. Figure 17B The bar chart shows the increase in ammonia levels over time in the superammonia model. As the figure shows, the ammonia level increases significantly to 227 μmol / L within 150 minutes.

[0626] In parallel experiments, following ALF induction as described above, animals were connected to a plasma apheresis system equipped with the device of this disclosure, referred herein as AAPC-300 (AMMONIA ADSORPTION PLASMACOLUMN (AAPC-300), PlasFree's ammonia absorber), which contains the conjugate of this disclosure to filter ammonia during plasma exchange. At the end of each blood filtration cycle, ammonia levels were monitored and recorded. Preliminary results showed a significant reduction in ammonia levels from 227 μmol / L to 65 μmol / L, thus confirming the feasibility of the method disclosed herein for ammonia in vivo / ex vivo depleted subjects.

[0627] Example 3

[0628] Depleting ammonium from human blood plasma

[0629] The inventors then evaluated the ability of the disclosed conjugate and device to deplete ammonium from ammonium-rich human plasma units. For example... Figure 18 As shown in the illustrative embodiment, the human plasma bag is connected via a flow regulator to the device of this disclosure (also known as AAPC-300) containing approximately 270 ml to 300 ml of the conjugate disclosed herein. As shown, filtered plasma is collected in the bag. The ammonia level in the filter bag is measured by ELISA, as... Figure 19 As shown, ammonia levels decreased significantly from approximately 120 μmol / L to approximately 20 μmol / L (a reduction of 1 / 6).

[0630] Therefore, these results confirm the feasibility of using the methods and apparatus disclosed in this invention to prepare readily available ammonia-free or ammonia-reduced blood products.

Claims

1. An apparatus comprising: - A housing having at least one fluid inlet port and at least one fluid outlet port; - The housing includes at least one chamber defining a control volume in fluid communication with the at least one fluid inlet port and the at least one fluid outlet port; The controlled volume contains at least one of the following substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates, the conjugate having the structure of Formula I, the conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group; Formula I Where n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines.

2. The apparatus of claim 1, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

3. The apparatus according to claim 1, wherein the linker comprises a straight-chain alkane and m carbonyl groups.

4. The apparatus of claim 3, wherein the straight-chain alkane is saturated or unsaturated.

5. The apparatus according to claim 4, wherein the straight-chain alkane is unsaturated.

6. The apparatus of claim 5, wherein the straight-chain alkane contains between one and three double bonds.

7. The apparatus according to any one of claims 1 to 6, wherein the amine is ammonia.

8. The apparatus according to any one of claims 1 to 6, wherein the linker is connected via a straight bond at the m-th carbonyl group ( ) or through another short alkane chain ( The trap is covalently connected in a manner that X is an integer in the range of 1 to 3.

9. The apparatus according to any one of claims 3 to 6, wherein the trapping agent is a strong acid capable of capturing ammonia.

10. The apparatus of claim 9, wherein the strong acid is sulfuric acid or any derivative thereof.

11. The apparatus of claim 10, wherein the length (n) of the straight-chain alkane is 15.

12. The apparatus according to any one of claims 1 to 6, comprising particles bonded to at least one linker, said at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, said conjugate having structural formula II: Formula II Where x is between 0 and 3.

13. The apparatus according to any one of claims 1 to 6, comprising particles bonded to at least one linker, said at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, said conjugate having structural formula III: Formula III Where x is between 0 and 3.

14. The apparatus according to claims 1 to 6, wherein the particles and the linker are covalently linked, and wherein the bond is a covalent bond realized via an amino group: Formula IV As shown in Formula IV.

15. The apparatus according to any one of claims 1 to 6, having structural formula V, wherein the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group. Formula V Where m is an integer between 5 and 10.

16. The apparatus according to any one of claims 1 to 6, wherein the particles are resin beads.

17. The apparatus of claim 16, wherein the resin beads comprise at least 4% agarose.

18. The apparatus of claim 16, wherein the size of the resin beads is in the range of 40µm to 170µm.

19. The apparatus according to any one of claims 1 to 6, wherein the apparatus includes a first barrier member and a second barrier member longitudinally spaced apart from each other via the control volume, the first barrier member and the second barrier member being respectively configured to allow fluid to flow through the respective barrier member in one direction and to block fluid from flowing through the respective barrier member in the opposite direction.

20. The apparatus of claim 19, wherein the first barrier member and the second barrier member are mounted in the apparatus in such a manner that fluid can flow from the at least one fluid inlet port through the apparatus to the at least one fluid outlet port while simultaneously blocking fluid from flowing from the fluid outlet port to the fluid inlet port.

21. The apparatus of claim 19, wherein each of the first barrier member and the second barrier member comprises a membrane made of a suitable material.

22. The apparatus according to any one of claims 1 to 6, wherein the housing comprises a shell, an inlet end cap, and an outlet end cap, wherein the shell includes an outer wall extending longitudinally between an inlet end and an outlet end of the shell, wherein the inlet end cap is configured to be hermetically mounted to the inlet end, and wherein the outlet end cap is configured to be hermetically mounted to the outlet end.

23. The device of claim 22, wherein the inlet end cap, the outlet end cap, and the housing are each made of a suitable medically compatible material.

24. The apparatus of claim 22, wherein the inlet end cap is configured as a self-locking cap relative to the housing and is configured to allow the inlet end cap to be locked in a sealing manner relative to the housing.

25. The apparatus of claim 24, further comprising a first self-locking arrangement configured to enable the inlet end cap to self-lock relative to the housing.

26. The apparatus of claim 25, wherein the first self-locking arrangement comprises a plurality of first wedge elements and a first flange arrangement, wherein the first wedge elements are disposed in the inlet end cap, and wherein the first flange arrangement is disposed in the housing at a position longitudinally spaced apart from the inlet end by a first distance, and wherein the first wedge elements are configured to cooperate with the first flange stop arrangement to provide self-locking of the inlet end cap relative to the housing.

27. The apparatus of claim 26, wherein each of the first wedge-shaped elements protrudes longitudinally away from the free end of the inlet end cap.

28. The apparatus of claim 26, wherein the first spacing is sufficient to ensure that when the inlet end cap is fully engaged with the housing, the respective free end of the inlet end cap is in abutment contact with the first flange arrangement.

29. The apparatus of claim 26, wherein the first flange stop arrangement includes a plurality of first stop elements corresponding to the plurality of first wedge elements, and wherein each of the first stop elements, when in abutment with a corresponding first wedge element, is used to prevent the inlet end cap from detaching from the housing.

30. The apparatus of claim 29, wherein the first flange stop arrangement includes a first flange including a plurality of first cuts corresponding to the first wedge element, and wherein each of the first cuts has a circumferential length and axial depth sufficient to allow a corresponding first wedge element to be received therein in a locking configuration.

31. The apparatus of claim 23, wherein the outlet end cap is configured as a self-locking cap relative to the housing and is configured to allow the outlet end cap to be locked in a sealing manner relative to the housing.

32. The apparatus of claim 31, further comprising a second self-locking arrangement configured to enable the outlet end cap to self-lock relative to the housing.

33. The apparatus of claim 32, wherein the second self-locking arrangement comprises a plurality of second wedge elements and a second flange arrangement, wherein the second wedge elements are disposed in the outlet end cap, and wherein the second flange arrangement is disposed in the housing at a position longitudinally spaced apart from the outlet end by a second distance, and wherein the second wedge elements are configured to cooperate with the second flange stop arrangement to provide self-locking of the outlet end cap relative to the housing.

34. The apparatus of claim 33, wherein each of the second wedge-shaped elements protrudes longitudinally away from the free end of the outlet end cap.

35. The apparatus of claim 33, wherein the second spacing is sufficient to ensure that when the outlet end cap is fully engaged with the housing, the respective free end of the outlet end cap is in abutment contact with the second flange arrangement.

36. The apparatus of claim 33, wherein the second flange stop arrangement comprises a plurality of second stop elements corresponding to the plurality of second wedge elements, and wherein each second stop element, when in abutment with a corresponding second wedge element, is used to prevent the outlet end cap from detaching from the housing.

37. The apparatus of claim 36, wherein the second flange stop arrangement includes a second flange having a plurality of second cuts corresponding to the second wedge element, and wherein each of the second cuts has a circumferential length and axial depth sufficient to allow a corresponding second wedge element to be received therein in a locking configuration.

38. The device according to any one of claims 1 to 6, wherein the control volume is between 250 ml and 350 ml.

39. The apparatus according to any one of claims 1 to 6, for depleting at least one amine from at least one liquid substance.

40. The apparatus of claim 39, wherein the amine is ammonia.

41. The apparatus of claim 40, wherein the liquid substance is a mammalian body fluid, the apparatus being used to deplete ammonia from the mammalian body fluid.

42. The apparatus according to any one of claims 1 to 6, wherein the conjugate has structural formula V, the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group. Formula V Where m is an integer between 5 and 10.

43. A system comprising: - At least one device as defined in any one of claims 1 to 6; - Apheresis blood component collection machine; - Blood mixing reservoir; as well as - Catheter system.

44. The system of claim 43, wherein the catheter system includes a first catheter configured to provide selective fluid communication between the apheresis component machine and the body of a subject in need, thereby enabling blood to flow from the body of the subject in need to the apheresis component machine.

45. The system of claim 43, wherein the catheter system includes a second catheter configured to provide fluid communication from the plasma outlet of the apheresis component machine to the at least one device, thereby enabling plasma separated from blood by the apheresis component machine to flow into the at least one device.

46. ​​The system of claim 43, wherein the catheter system includes a third catheter configured to provide fluid communication from the at least one device to the blood mixing reservoir, thereby enabling processed plasma processed by the at least one device to flow into the blood mixing reservoir.

47. The system of claim 43, wherein the catheter system includes a fourth catheter configured to provide fluid communication from the blood product outlet of the apheresis component machine to the blood mixing reservoir, thereby allowing other blood products separated from the blood by the apheresis component machine to flow into the blood mixing reservoir.

48. The system of claim 43, wherein the catheter system includes a fifth catheter configured to provide selective fluid communication between the blood mixing reservoir and the body of a subject in need, thereby enabling treated blood to flow from the blood mixing reservoir into the body of the subject in need.

49. The system of claim 43, comprising a plurality of said devices interconnected in series with respect to each other.

50. The system of claim 43, comprising a plurality of said means interconnected in parallel with each other via an inlet manifold coupled to each respective fluid inlet port and an outlet manifold coupled to each respective fluid outlet port.

51. The system of claim 43, comprising a first plurality of said devices, said groups being interconnected in parallel with each other via inlet manifolds coupled to each respective fluid inlet port and via outlet manifolds coupled to each respective fluid outlet port, wherein each said group comprises a corresponding second plurality of said devices, said second plurality of said devices being interconnected in series with each other within said respective group.

52. A battery for depleting ammonia from the bodily fluids of a mammal, comprising a plurality of means as defined in any one of claims 1 to 6.

53. An in vitro device comprising at least one conjugate, or at least one device comprising said conjugate, or connected to said at least one device or a series of devices, wherein the conjugate comprises particles bonded to at least one linker, said at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group. Formula I in, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines, and wherein the device comprises: - A housing having at least one fluid inlet port and at least one fluid outlet port; - The housing includes at least one chamber defining a control volume in fluid communication with the at least one fluid inlet port and the at least one fluid outlet port; The controlled volume contains at least one of the following substances: a conjugate, multiple conjugates, or at least one composition comprising the conjugate or multiple conjugates.

54. The in vitro device of claim 53, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

55. The external device of claim 53, wherein the device is defined as in any one of claims 1 to 6, and wherein the battery is defined as in claim 52.

56. The extracorporeal device according to claim 53, for depleting ammonia from the body fluids of a mammal.

57. A conjugate having structural formula I, the conjugate comprising particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group; Formula I in, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines.

58. The conjugate according to claim 57, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

59. The conjugate according to claim 57, wherein the linker comprises a straight-chain alkane and m carbonyl groups.

60. The conjugate according to claim 59, wherein the straight-chain alkane is saturated or unsaturated.

61. The conjugate according to claim 60, wherein the straight-chain alkane is unsaturated.

62. The conjugate according to claim 61, wherein the straight-chain alkane contains between one and three double bonds.

63. The conjugate according to any one of claims 57 to 62, wherein the amine is ammonia.

64. The conjugate according to any one of claims 57 to 62, wherein the linking group is connected via a straight bond at the m-th carbonyl group ( ) or linked through another short alkane chain ( X is covalently attached to the trap in a manner that X is an integer in the range of 1 to 3.

65. The conjugate according to any one of claims 59 to 62, wherein the trapping agent is a strong acid capable of trapping ammonia.

66. The conjugate according to claim 65, wherein the strong acid is sulfuric acid or any derivative thereof.

67. The conjugate according to claim 66, wherein the length (n) of the straight-chain alkane is 15.

68. The conjugate according to any one of claims 57 to 62, comprising particles bonded to at least one linker, said at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and an acid A covalently bonded to the m-th carbonyl group, said conjugate having structural formula II: Formula II Where x is between 0 and 3.

69. The conjugate according to any one of claims 57 to 62, comprising particles bonded to at least one linker, said at least one linker comprising a chain of 15 carbon atoms covalently bonded to between 5 and 10 carbonyl groups (m); and a sulfonic acid covalently bonded to the m-th carbonyl group, said conjugate having structural formula III: Formula III Where x is between 0 and 3.

70. The conjugate according to claims 57 to 62, wherein the particles and the linker are covalently linked, and wherein the bond is a covalent bond realized via an amino group: Formula IV As shown in Formula IV.

71. The conjugate according to any one of claims 57 to 62, having structural formula V, the conjugate comprising particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group. Formula V Where m is an integer between 5 and 10.

72. The conjugate according to any one of claims 57 to 62, wherein the particles are resin beads.

73. The conjugate according to claim 72, wherein the resin beads comprise at least 4% agarose.

74. The conjugate according to claim 72, wherein the size of the resin beads is in the range of 40µm to 170µm.

75. A composition comprising a plurality of conjugates, wherein each conjugate comprises particles, at least one linker and at least one trapping agent A, or any derivative thereof, said conjugate comprising particles bonded to at least one linker, said at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group; Formula I in, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines.

76. The composition of claim 75, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

77. The composition of claim 75, wherein the conjugate is defined as in any one of claims 57 to 62.

78. The composition according to claim 75, used to deplete at least one amine from at least one liquid substance.

79. The composition according to claim 78, wherein the amine is ammonia.

80. The composition of claim 79, wherein the liquid substance is a mammalian body fluid, and the plurality of conjugates are used to deplete ammonia from the mammalian body fluid.

81. An in vitro or ex vivo method for depleting at least one amine from a liquid substance, the method comprising the steps of: (i) subjecting the liquid substance to an affinity depletion process specifically for the at least one amine; as well as (ii) Recover the liquid from which at least one amine has been depleted, obtained in step (i); The affinity depletion procedure includes contacting the liquid substance with an effective amount of at least one conjugate, multiple conjugates, or a composition containing the conjugate or multiple conjugates, or applying the liquid substance to a device, battery, or external device containing the conjugate, wherein each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group. Formula I Wherein, n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind the amine.

82. The in vitro or ex vivo method according to claim 81, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

83. The in vitro or ex vivo method according to claim 81, wherein the liquid substance is a mammalian body fluid or any product thereof.

84. The in vitro or ex vivo method according to any one of claims 81 to 83, wherein the at least one amine is ammonia, and the method is used to deplete ammonia from the body fluids of a mammal.

85. The in vitro or ex vivo method according to any one of claims 81 to 83, wherein the conjugate is as defined in claim 57, the plurality of conjugates or compositions are as defined in claim 75, the device is as defined in any one of claims 1 to 6, the system is as defined in claim 43, the battery is as defined in claim 52, and the apparatus is as defined in claim 53.

86. Use of an effective amount of one or more conjugates in the preparation of a product for depleting at least one amine from the bodily fluids of a subject in need via an in vitro procedure, wherein the preparation of the product is carried out by a method comprising the following steps: (i) Transferring the subject's bodily fluids into an external device; (ii) subjecting the body fluid to an affinity depletion procedure specifically for at least one amine, wherein the depletion is performed before, during, or after blood is transferred into and from the device, thereby obtaining an in vitro body fluid of the subject depleted of at least one amine; as well as (iii) Reintroduce or return the bodily fluids obtained in step (ii) to the subject; The affinity depletion procedure includes contacting the bodily fluid with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or in a device or battery connected to the external device, wherein each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group. Formula I Where n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to trap or bind amines.

87. The use according to claim 86, wherein the amine is at least one of methylamine, dimethylamine, or trimethylamine.

88. The use according to claim 86, wherein the conjugate is defined as in any one of claims 57 to 58, the plurality of conjugates or compositions is defined as in claim 75, the device is defined as in any one of claims 1 to 6, the system is defined as in claim 43, the battery is defined as in claim 52, and the apparatus is defined as in claim 53.

89. The use according to claim 86 or 87, wherein the conjugate has structural formula V, the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group. Formula V Where m is an integer between 5 and 10.

90. Use of an effective amount of one or more conjugates in the preparation of a medicament for treating, preventing, ameliorating, or inhibiting a condition or pathological condition associated with elevated blood ammonia levels in a subject of need by depleting ammonia from the body fluids of the subject of need through an in vitro procedure, wherein the medicament is prepared by a method comprising the following steps: a. Transfer the subject's bodily fluids to an external device; b. subjecting the body fluid to an affinity depletion procedure specifically for the ammonia, wherein the depletion is performed before, during, or after blood is transferred into and from the device, thereby obtaining an ammonia-depleted in vitro body fluid of the subject; as well as c. Reintroduce or return the bodily fluids obtained in step (b) to the subject; The affinity depletion procedure includes contacting the bodily fluid with an effective amount of the conjugate, multiple conjugates, or a combination thereof contained within the external device or in a device or battery connected to the external device, wherein each conjugate comprises particles bonded to at least one linker, the at least one linker comprising a chain of n carbon atoms covalently bonded to m carbonyl groups; and at least one trapping agent A covalently bonded to the mth carbonyl group. Formula I Where n is an integer in the range of 5 to 15, and m is an integer in the range of 5 to 10, wherein the trapping agent A is characterized by having the ability to capture or bind ammonia.

91. The use according to claim 90, wherein the conjugate is defined as any one of claims 57 to 62, the plurality of conjugates or compositions is defined as claimed 75, the device is defined as claimed as any one of claims 1 to 6, the system is defined as claimed 43, the battery is defined as claimed 52, and the apparatus is defined as claimed 53.

92. The use according to claim 90, wherein the conjugate has structural formula V, the conjugate comprises particles covalently bonded to at least one linker, the at least one linker comprising a chain of 15 carbon atoms covalently bonded to m carbonyl groups; and a sulfonic acid covalently bonded to the mth carbonyl group. Formula V Where m is an integer between 5 and 10.

93. The use according to claim 90, wherein the condition associated with elevated blood ammonia levels is a chronic liver or lung condition and / or cognitive decline, and / or hyperammonemia and related conditions.

94. The use according to claim 93, wherein the liver condition is hepatic encephalopathy and any related condition.

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