WO2023064357A1 - Compositions pharmaceutiques destinées au traitement d'une lithiase - Google Patents

Compositions pharmaceutiques destinées au traitement d'une lithiase Download PDF

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WO2023064357A1
WO2023064357A1 PCT/US2022/046405 US2022046405W WO2023064357A1 WO 2023064357 A1 WO2023064357 A1 WO 2023064357A1 US 2022046405 W US2022046405 W US 2022046405W WO 2023064357 A1 WO2023064357 A1 WO 2023064357A1
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composition
nonabsorbable
nonabsorbable composition
capacity
target species
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PCT/US2022/046405
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English (en)
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Dawn Parsell OTTO
Vandana Mathur
Gerrit Klaerner
David A. BUSHINSKY
Navdeep TANGRI
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Tricida, Inc.
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Publication of WO2023064357A1 publication Critical patent/WO2023064357A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen

Definitions

  • the present disclosure relates to the medical use of a nonabsorbed composition, preferably veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane), for the treatment of a lithiasis disorder.
  • a nonabsorbed composition preferably veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane
  • a lithiasis disorder is a disorder associated with the formation of crystalline minerals in any organ or tissue including, but not limited to, the kidneys and urinary collecting system and vasculature.
  • a lithiasis disorder may lead to the formation of calculi or stones inside the kidneys or the urinary tract (e.g., ureters or bladder).
  • a kidney stone also called renal calculi, nephrolithiasis or urolithiasis
  • a kidney stone is a crystalline mineral formed within the kidney or urinary tract and are a common cause of blood in the urine. Diet, excess body weight, some medical conditions, and certain supplements and medications are among the many causes of kidney stones. While some types of stones are less likely to form at higher urine pH (Wagner CA, Mohebbi N. J Nephrol Suppl 16: S165-9, 2010), stones often form when the urine becomes concentrated, allowing minerals to crystallize and stick together.
  • Calcium oxalate is a common constituent of renal calculi and relatively large crystals of this salt are frequently found in freshly voided urine from patients with recurrent calcium-containing stones.
  • Current treatments of calcium oxalate monohydrate (COM) stone disease include increased water intake, diet supervision, and alkalization agents, which collectively reduce calcium oxalate super saturation in urine.
  • Hydrochlorothiazide, sodium potassium phosphate, potassium citrate, and allopurinol are drugs available for the treatment of calcium oxalate stone disease and reported to reduce its recurrence. While these treatments can be effective, they do not completely prevent stone recurrence. In addition, many of the current treatments have significant adverse effects.
  • a pharmaceutical composition for the treatment of a lithiasis disorder wherein the nonabsorbable composition has the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • a further aspect of the present disclosure is directed to the medical use of a pharmaceutical composition for the treatment of a lithiasis disorder in a subject afflicted chronic kidney disease (“CKD”) wherein the pharmaceutical composition comprises a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • CKD chronic kidney disease
  • a further aspect of the present disclosure is directed to the medical use of a pharmaceutical composition for the treatment of a lithiasis disorder in a subject afflicted metabolic acidosis wherein the pharmaceutical composition comprises a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • a further aspect of the present disclosure is directed to the medical use of a pharmaceutical composition for the treatment of a lithiasis disorder in a subject afflicted eubicarbonatemic acidosis wherein the pharmaceutical composition comprises a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • a further aspect of the present disclosure is directed to the medical use of a pharmaceutical composition for the treatment of a lithiasis disorder wherein the pharmaceutical composition comprises a crosslinked poly(allylamine) polymer.
  • the poly(allylamine) polymer is veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • a further aspect of the present disclosure is directed to the medical use of a pharmaceutical composition for the treatment of a lithiasis disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the nonabsorbable composition has the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • a further aspect of the present disclosure is directed to a method for the treatment of a lithiasis disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the method comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • a further aspect of the present disclosure is a method of treating a lithiasis disorder, the method comprising oral administration of a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • a further aspect of the present disclosure is a method of treating an individual afflicted with a lithiasis disorder, the method comprising oral administration of a pharmaceutical composition comprising a crosslinked poly(allylamine) polymer.
  • the poly(allylamine) polymer is veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • a further aspect of the present disclosure is a method of treatment of a lithiasis disorder in a subject afflicted chronic kidney disease (“CKD”) wherein the method comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • CKD chronic kidney disease
  • a further aspect of the present disclosure is a method of treatment of a lithiasis disorder in a subject afflicted metabolic acidosis wherein the method comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • a further aspect of the present disclosure is a method of treatment of a lithiasis disorder in a subject afflicted eubicarbonatemic acidosis wherein the method comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • a further aspect of the present disclosure is a nonabsorbable composition for use in a method of treatment of an individual afflicted with a lithiasis disorder, wherein the method comprises oral administration of the nonabsorbable composition and the nonabsorbable composition has the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • the target species is hydrochloric acid.
  • the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • the nonabsorbable composition is veverimer.
  • a further aspect of the present disclosure is a method of treatment of an individual afflicted with a lithiasis disorder, the method comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • the target species is hydrochloric acid.
  • the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • the nonabsorbable composition is veverimer.
  • a further aspect of the present disclosure is a method of reducing lithiasis-related inpatient hospitalization rates, the method comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • the target species is hydrochloric acid.
  • the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • the nonabsorbable composition is veverimer.
  • a further aspect of the present disclosure is a method of reducing kidney stone-related inpatient hospitalization rates, the method comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • the target species is hydrochloric acid.
  • the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • the nonabsorbable composition is veverimer.
  • Fig. 1 is a graphic depicting the design for the study cohort described in Example 1 .
  • Investigators had full access to the database extract but no direct access to the Optum database.
  • Fig. 2 is a bar graph depicting the percentage of patients in the full study cohort developing post-index kidney stones (unadjusted), as more fully described in Example 1 .
  • the median follow-up duration was 3.2 years. Data depicted are proportions and 95% confidence intervals.
  • Fig. 3 is a bar graph depicting the kidney stone-related inpatient hospitalization rate per 1000 patient-years in the full study cohort (unadjusted), as more fully described in Example 1 .
  • the median follow-up duration was 3.2 years. Data depicted are proportions and 95% confidence intervals.
  • Fig. 4 is a bar graph depicting the percentage of patients with a history of kidney stones developing post-index kidney stones (unadjusted), as more fully described in Example 1 .
  • Fig. 5 is a chart depicting the Cox proportional hazard ratios for time to incident kidney stone (adjusted), as more fully described in Example 1.
  • the term “adult” refers to an individual over 18 years of age.
  • alicyclic means a saturated monocyclic group of 3 to 8 carbon atoms and includes cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • aliphatic denotes saturated and non-aromatic unsaturated hydrocarbyl moieties having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms, one to about ten carbon atoms, one to about eight carbon atoms, or even one to about four carbon atoms.
  • the aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like, and alkenyl moieties of comparable chain length.
  • alkanol denotes an alkyl moiety that has been substituted with at least one hydroxyl group.
  • alkanol groups are “lower alkanol” groups comprising one to six carbon atoms, one of which is attached to an oxygen atom.
  • lower alkanol groups comprise one to three carbon atoms.
  • alkenyl group encompasses linear or branched carbon radicals having at least one carbon-carbon double bond.
  • alkenyl group can encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof.
  • alkenyl group for example and without being limited thereto, can encompass two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms.
  • alkenyl groups are "lower alkenyl” groups having two to about four carbon atoms.
  • alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, vinyl, butenyl and 4-methylbutenyl.
  • alkenyl group and “lower alkenyl group” encompass groups having "cis” or "trans” orientations, or alternatively, "E” or "Z” orientations.
  • alkyl group as used, either alone or within other terms such as “haloalkyl group,” “aminoalkyl group” and “alkylamino group”, encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are "lower alkyl” groups having one to about six carbon atoms.
  • lower alkyl groups have one to four carbon atoms.
  • alkylamino group refers to amino groups directly attached to the remainder of the molecule via the nitrogen atom of the amino group and wherein the nitrogen atom of the alkylamino group is substituted by one or two alkyl groups.
  • alkylamino groups are "lower alkylamino" groups having one or two alkyl groups of one to six carbon atoms, attached to a nitrogen atom. In other embodiments, lower alkylamino groups have one to three carbon atoms.
  • Suitable “alkylamino” groups may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, N,N-diethylamino, pentamethyleneamine and the like.
  • amine or "amino" as used alone or as part of another group, represents a group of formula -N(Xs)(X9), wherein Xs and X9 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, heteroaryl, or heterocyclo, or Xs and X9 taken together form a substituted or unsubstituted alicyclic, aryl, or heterocyclic moiety, each as defined in connection with such term, typically having from 3 to 8 atoms in the ring.
  • aminoalkyl group encompasses linear or branched alkyl groups having one to about ten carbon atoms, any one of which may be substituted with one or more amino groups, directly attached to the remainder of the molecule via an atom other than a nitrogen atom of the amine group(s).
  • the aminoalkyl groups are "lower aminoalkyl” groups having one to six carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • anion exchange material and “cation exchange material” take their normal meaning in the art.
  • anion exchange material and “cation exchange material” refer to materials that exchange anions and cations, respectively.
  • Anion and cation exchange materials are typically water-insoluble substances which can exchange some of their cations or anions, respectively, for similarly charged anions or cations contained in a medium with which they are in contact.
  • Anion exchange materials may contain positively charged groups, which are fixed to the backbone materials and allow passage of anions but reject cations. A non- exhaustive list of such positively charged groups includes: amino group, alkyl substituted phosphine, and alkyl substituted sulphides.
  • a non-exhaustive list of cation or anion exchange materials includes: clays (e.g., bentonite, kaolinite, and illite), vermiculite, zeolites (e.g., analcite, chabazite, sodalite, and clinoptilolite), synthetic zeolites, polybasic acid salts, hydrous oxides, metal ferrocyanides, and heteropolyacids.
  • Cation exchange materials can contain negatively charged groups fixed to the backbone material, which allow the passage of cations but reject anions.
  • a non- exhaustive list of such negatively charged groups includes: sulphate, carboxylate, phosphate, and benzoate.
  • aromatic group or "aryl group” means an aromatic group having one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • an aromatic group is one, two or three rings.
  • Monocyclic aromatic groups may contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms in the ring.
  • Typical polycyclic aromatic groups have two or three rings.
  • Polycyclic aromatic groups having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the rings.
  • aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • bearing is used to describe a crosslinked polymer that is substantially spherical in shape.
  • bicarbonate equivalent is used to describe an organic acid or anion that yields bicarbonate when metabolized. Citrate and succinate are exemplary bicarbonate equivalents.
  • binding as used herein in connection with a polymer and one or more ions, that is, a cation (e.g. “proton-binding” polymer) and an anion, is an "ionbinding" polymer and/or when it associates with the ion, generally though not necessarily in a non-covalent manner, with sufficient association strength that at least a portion of the ion remains bound under the in vitro or in vivo conditions in which the polymer is used for sufficient time to effect a removal of the ion from solution or from the body.
  • blood bicarbonate value shall mean the concentration of bicarbonate in a subject’s blood plasma or serum.
  • ceramic material takes its normal meaning in the art.
  • the term “ceramic material” refers to an inorganic, nonmetallic, solid material comprising metal, nonmetal or metalloid atoms primarily held in ionic and covalent bonds.
  • a non-exhaustive list of examples of ceramic materials includes: barium titanate, bismuth strontium calcium copper oxide, boron oxide, earthenware, ferrite, lanthanum carbonate, lead zirconate, titanate, magnesium diboride, porcelain, sialon, silicon carbide, silicon nitride, titanium carbide, yttrium barium copper oxide, zinc oxide, zirconium dioxide, and partially stabilised zirconia.
  • the term “clinically significant increase” as used herein in connection with a treatment refers to a treatment that improves or provides a worthwhile change in an individual from a dysfunctional state back to a relatively normal functioning state, or moves the measurement of that state in the direction of normal functioning, or at least a marked improvement to untreated.
  • a number of methods can be used to calculate clinical significance.
  • a non-exhaustive list of methods for calculating clinical significance includes: Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman- Arrindell, and Hierarchical Linear Modeling (HLM).
  • crosslinker encompasses hydrocarbyl or substituted hydrocarbyl, linear or branched molecules capable of reacting with any of the described monomers, or the infinite polymer network, as described in Formula 1 , more than one time.
  • the reactive group in the crosslinker can include, but is not limited to alkyl halide, epoxide, phosgene, anhydride, carbamate, carbonate, isocyanate, thioisocyanate, esters, activated esters, carboxylic acids and derivatives, sulfonates and derivatives, acyl halides, aziridines, a,p-unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl groups, vinyl, allyl, acrylate, methacrylate, acrylamide, methacrylamide, styrenic, acrylonitriles and combinations thereof.
  • the crosslinker’s reactive group will include alkyl halide, epoxide, anhydrides, isocyanates, allyl, vinyl, acrylamide, and combinations thereof. In one such embodiment, the crosslinker’s reactive group will be alkyl halide, epoxide, or allyl.
  • diallylamine denotes an amino moiety having two allyl groups.
  • dry polymer refers to polymers that contain no more than 5% by weight of a non-polymer swelling agent or solvent. Often the swelling agent/solvent is water remaining at the end of a purification. This is generally removed by lyophilization or oven drying before storage or further crosslinking of a preformed amine polymer. The amount of swelling agent/solvent can be measured by heating (e.g., heating to 100-200°C) and measuring the resulting change in weight. This is referred to a “loss on drying” or “LOD.”
  • eGFR estimated glomerular filtration rate
  • Creatinine is a commonly used endogenous filtration marker in clinical practice and several equations have been proposed for estimating the glomerular filtration rate.
  • all eGFR values may be determined according to the CKD-EPI equation (Levey et al., A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612):
  • GFR 41 * min(Scr/K,1) a * max(Scr/K, 1) 1 209 * 0.993 A 9 e * 1.018 [if female] * 1.159 [if black] wherein Scr is serum creatinine (mg/dL), K is 0.7 for females and 0.9 for males, a is - 0.329 for females and -0.411 for males, min indicates the minimum of Scr/K or 1 , and max indicates the maximum of Scr/K or 1 .
  • gel is used to describe a crosslinked polymer that has an irregular shape.
  • GFR glomerular filtration rate
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl group encompasses groups wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically encompassed are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups including perhaloalkyl.
  • a monohaloalkyl group for example, may have either an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • “Lower haloalkyl group” encompasses groups having 1-6 carbon atoms.
  • lower haloalkyl groups have one to three carbon atoms.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • heteroaliphatic describes a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or unsaturated (but not aromatic), containing one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron.
  • a heteroatom atom may be a part of a pendant (or side) group attached to a chain of atoms (e.g., -CH(OH)- - CH(NH2)- where the carbon atom is a member of a chain of atoms) or it may be one of the chain atoms (e.g., -ROR- or -RNHR- where each R is aliphatic).
  • Heteroaliphatic encompasses heteroalkyl and heterocyclo but does not encompass heteroaryl.
  • heteroalkyl describes a fully saturated heteroaliphatic moiety.
  • heteroaryl means a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • heteroaryl and “aryl” are mutually exclusive.
  • Heteroarylene means a divalent heteroaryl radical.
  • heteroatom means an atom other than carbon and hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorous, nitrogen, boron and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.
  • heterocyclo means a saturated or unsaturated group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom such as N, O, B, P and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -C(O)- group.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • hydrocarbon group or “hydrocarbyl group” means a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms.
  • Hydrocarbon groups may have a linear or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbon groups may have one or more double bonds, one or more triple bonds, or combinations thereof. Typical unsaturated hydrocarbon groups have one or two double bonds or one triple bond; more typically unsaturated hydrocarbon groups have one double bond.
  • Initiator is a term used to describe a reagent that initiates a polymerization.
  • the term “measured glomerular filtration rate” or “mGFR” refers to a measurement of the glomerular filtration rate using any chemical (e.g., inulin, iothalamate, iohexol, etc.) that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys according to standard technique.
  • chemical e.g., inulin, iothalamate, iohexol, etc.
  • the term “Michael acceptor” takes its normal meaning in the art.
  • the term “Michael acceptor” refers to activated olefins, such as a,p-unsaturated carbonyl compounds.
  • a Michael acceptor can be a conjugated system with an electron withdrawing group, such as cyano, keto or ester.
  • An electron withdrawing group such as cyano, keto or ester.
  • a non-exhaustive list of examples of Michael acceptors includes: vinyl ketones, alkyl acrylates, acrylo nitrile, and fumarates.
  • MW/N molecular weight per nitrogen
  • nonabsorbable takes its normal meaning in the art. Therefore, if something is nonabsorbable it is not absorbed during its passage through the human Gl tract. This could be measured by any appropriate means.
  • One option known to the skilled person would be to examine faeces to see if the nonabsorbable material is recovered after passing through the Gl tract. As a practical matter, the amount of a nonabsorbable material recovered in this scenario will never be 100% of the material administered. For example, about 90 - 99% of the material might be recovered from the faeces.
  • Another option known to the skilled person would be to look for the presence of the material in the lymph, blood, interstitial fluid, secretions from various organs (e.g., pancreas, liver, gut, etc.) or in the body of organs (e.g., liver, kidney, lungs, etc.) as oral administration of a nonabsorbable material would not result in an increase in the amount of that material in these matrices and tissues.
  • organs e.g., pancreas, liver, gut, etc.
  • body of organs e.g., liver, kidney, lungs, etc.
  • Nonabsorbable compositions may be particulate compositions that are essentially insoluble in the human Gl tract and have a particle size that is large enough to avoid passive or active absorption through the human Gl tract.
  • nonabsorbable compositions is meant to imply that the substance does not enter the lymph, blood, interstitial fluids or organs through the main entry points of the human Gl tract, namely by paracellular entry between gut epithelial cells, by endocytic uptake through gut epithelial cells, or through entry via M cells comprising the gut epithelial antigen sampling and immune surveillance system (Jung, 2000), either through active or passive transport processes.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes embodiments in which the heterocyclyl group is substituted with an alkyl group and embodiments in which the heterocyclyl group is not substituted with alkyl.
  • Particle size is measured by wet laser diffraction using Mie theory. Particles are dispersed in an appropriate solvent, such as water or methanol, and added to the sample chamber to achieve red channel obscuration of 10-20%. Sonication may be performed, and a dispersing agent, such as a surfactant (e.g. Tween-80), may be added in order to disrupt weak particle-particle interactions.
  • a dispersing agent such as a surfactant (e.g. Tween-80)
  • the refractive index setting of the particles used for size distribution calculation is selected to minimize artifacts in the results and the R parameter value, determined by the laser diffraction software.
  • the D(0.1 ), D(0.5), and D(0.9) values characterizing the particle size distribution by volumebasis are recorded.
  • “Pharmaceutically acceptable” as used in connection with a carrier, diluent or excipient means a carrier, diluent or an excipient, respectively, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable for veterinary use and/or human pharmaceutical use.
  • post polymerization crosslinking is a term that describes a reaction to an already formed bead or gel, where more crosslinking is introduced to the already formed bead or gel to create a bead or gel that has an increased amount of crosslinking.
  • post polymerization modification is a term that describes a modification to an already formed bead or gel, where a reaction or a treatment introduces an additional functionality. This functionality can be linked either covalently or non-covalently to the already formed bead.
  • QAA quaternized amine assay
  • the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (e.g. 25 mg dry mas) in 10 ml_ of QAA buffer.
  • the mixture is incubated at 37 °C for ⁇ 16 hours with agitation on a rotisserie mixer. After incubation and mixing, 600 microliters of supernatant is removed and filtered using a 800 microliter, 0.45 micrometer pore size, 96-well poly propylene filter plate. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000Xg for 1 minute to filter the samples. After filtration into the collection plate, the respective filtrates are diluted appropriately before measuring for chloride content.
  • the IC method e.g. ICS-2100 Ion Chromatography, Thermo Fisher Scientific
  • Thermo Fisher Scientific used for the analysis of chloride content in the filtrates consists of a 15 mM KOH mobile phase, an injection volume of 5 microliters, with a run time of three minutes, a washing/rinse volume of 1000 microliters, and flow rate of 1 .25 mL /min.
  • renal lithiasis refers to the disorder caused by the presence of calculi or stones inside the kidneys or the urinary tract (ureters, bladder).
  • short chain carboxylic acid or “short chain fatty acid” take their normal meaning in the art.
  • the terms “short chain carboxylic acid” or “short chain fatty acid” refer to carboxylic acids having a chain length of 0, 1 , 2, 3, 4, 5 or 6 carbon atoms long.
  • a non-exhaustive list of examples of short chain carboxylic acids includes: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid.
  • Simulated Gastric Fluid or “SGF” Assay describes a test to determine total chloride binding capacity for a test polymer using a defined buffer that simulates the contents of gastric fluid as follows: Simulated gastric fluid (SGF) consists of 35 mM NaCI, 63 mM HCI, pH 1 .2. To perform the assay, the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SGF buffer. The mixture is incubated at 37 °C overnight for -12-16 hours with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SGF binding data or binding capacities recited herein are determined in a time period of this duration.
  • the tubes containing the polymer are centrifuged for 2 minutes at 500-1 OOOXg to pellet the test samples. Approximately 750 microliters of supernatant are removed and filtered using an appropriate filter, for example, a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate.
  • an appropriate filter for example, a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate.
  • the unit is centrifuged at 1000Xg for 1 minute to filter the samples.
  • a syringe filter may be used in lieu of the filter plate, to retrieve ⁇ 2-4 mL of filtrate into a 15 mL container.
  • the respective filtrates are diluted 4X with water and the chloride content of the filtrate is measured via ion chromatography (IC).
  • IC ion chromatography
  • Dionex ICS-2100 Thermo Scientific
  • ICS-2100 Thermo Scientific
  • Binding capacity expressed as mmol chloride/g polymer where Cl start corresponds to the starting concentration of chloride in the SGF buffer, Cl eq corresponds to the equilibrium value of chloride in the diluted measured filtrates after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml.
  • SIB Simulated Small Intestine Inorganic Buffer
  • SIB a test to determine the chloride and phosphate binding capacity of free amine test polymers in a selective specific interfering buffer assay (SIB).
  • the buffer used for the SIB assay comprises 36 mM NaCI, 20 mM NaH2PO4, 50 mM 2-(N- morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
  • MES 2-(N- morpholino)ethanesulfonic acid
  • the SIB buffer contains concentrations of chloride, phosphate and pH that are present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, Van Lente F, Khandwala F, Purich E, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;60(3):351-5, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci.
  • the free amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SIB buffer. The mixture is incubated at 37 °C for 1 hour with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SIB binding data or binding capacities recited herein are determined in a time period of this duration. After incubation and mixing, the tubes containing the polymer are centrifuged for 2 minutes at 1000Xg to pellet the test samples.
  • a syringe filter (0.45 micrometer) may be used in lieu of the filter plate, to retrieve ⁇ 2-4 mL of filtrate into a 15 mL vial.
  • the respective filtrates are diluted before measuring for chloride or phosphate content.
  • the filtrates under analysis are diluted 4X with water.
  • the chloride and phosphate content of the filtrate is measured via ion chromatography (IC).
  • IC ion chromatography
  • Dionex ICS-2100 Thermo Scientific
  • ICS-2100 Thermo Scientific
  • Cistart corresponds to the starting concentration of chloride in the SIB buffer
  • Cltinai corresponds to the final value of chloride in the measured diluted filtrates after exposure to the test polymer
  • 4 is the dilution factor
  • 2.5 is the polymer concentration in mg/ml.
  • Binding capacity expressed as mmol phosphate/g polymer (P start ⁇ Pfinal) x 2.5
  • Pstart corresponds to the starting concentration of phosphate in the SIB buffer
  • Pfinai corresponds to the final value of phosphate in the measured diluted filtrates after exposure to the test polymer
  • 4 is the dilution factor
  • 2.5 is the polymer concentration in mg/ml.
  • substituted hydrocarbyl denotes hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moieties which are substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
  • substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • ‘Swelling Ratio” or simply ‘ Swelling” describes the amount of water absorbed by a given amount of polymer divided by the weight of the polymer aliquot.
  • the method used to determine the Swelling Ratio for any given polymer comprised the following:
  • step (b) the weight of swollen polymer plus tube (Weight B) is recorded.
  • a "target ion” is an ion to which the polymer binds, and usually refers to the major ions bound by the polymer, or the ions whose binding to the polymer is thought to produce the therapeutic effect of the polymer (e.g., proton and chloride binding which leads to net removal of HCI).
  • Treating” or “treatment” of a disease includes (i) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (ii) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. Inhibiting the disease, for example, would include prophylaxis.
  • trimethylamine denotes an amino moiety having three allyl groups.
  • uric acid crystals or “uric acid stones” includes all such process or conditions which imply/induce the formation of solid precipitates in the urine wherein this substance is involved.
  • a lithiasis disorder may be treated using pharmaceutical compositions comprising a nonabsorbable composition having the capacity to remove clinically significant quantities of protons, the conjugate base of one or more strong acids, and/or one or more strong acids.
  • An individual afflicted with a lithiasis disorder may thus be treated by oral administration of a pharmaceutical composition comprising the nonabsorbable composition which then transits the individual’s digestive system, binds a target species (protons, one or more conjugate base(s) of a strong acid and/or one or more strong acid(s)) as it transits the digestive system, and removes the bound target species by normal biological function (defecation).
  • the lithiasis disorder may be any disorder associated with the formation of a crystalline mineral in an organ or tissue of an individual including, but not limited to, the kidneys and urinary collecting system and vasculture.
  • a lithiasis disorder may lead to the formation of calculi or stones inside the kidneys or the urinary tract (e.g., ureters or bladder) of the afflicted individual.
  • Additional examples include the formation of crystalline minerals associated with or of the following types: calciphylaxis, vascular calcification, tumor lysis syndrome, kidney or bladder stones (e.g. calcium phosphate, calcium citrate, uric acids, cystine, and struvite).
  • an individual will be treated in accordance with the present disclosure upon medical evidence of an existing lithiasis disorder or risk for such a disorder (e.g., urinary supersaturation of the crystalline mineral), or risk of rapid release of the crystalline mineral (e.g., tumor lysis syndrome) or to reduce the risk of recurrence of such a condition.
  • a lithiasis disorder or risk for such a disorder e.g., urinary supersaturation of the crystalline mineral
  • risk of rapid release of the crystalline mineral e.g., tumor lysis syndrome
  • the individual afflicted with a lithiasis disorder may be at any stage of chronic kidney disease, which includes both individuals who have reached end-stage renal disease who have received a kidney transplant or who are on chronic dialysis as well as those who have not yet reached ESRD.
  • the afflicted individual has not yet reached end stage renal disease (“ESRD”), sometimes also referred to as end stage chronic kidney disease, and is not yet on dialysis (e.g., the individual has an mGFR (or eGFR) of at least 15 mL/min/1 .73 m 2 ).
  • the afflicted individual will be Stage 3B CKD (/'.e., the individual has an mGFR (or eGFR) in the range of 30-44 mL/min/1 .73 m 2 for at least three months).
  • the afflicted individual will be Stage 3A CKD (i.e., the individual has an mGFR (or eGFR) in the range of 45-59 mL/min/1.73 m 2 for at least three months).
  • the afflicted individual has an mGFR or an eGFR of less than 60 mL/min/1 .73 m 2 for at least three months.
  • the afflicted individual has an mGFR or an eGFR of less than 45 mL/min/1 .73 m 2 for at least three months.
  • the afflicted individual has an mGFR or an eGFR of less than 30 mL/min/1 .73 m 2 for at least three months.
  • the afflicted individual has an mGFR or an eGFR of 15-30, 15-45, 15-60, 30-45 or even 30-60 mL/min/1 .73 m 2 for at least three months.
  • the afflicted individual has Stage 3A CKD, Stage 3B CKD, or Stage 4 CKD.
  • the individual afflicted with a lithiasis disorder may also be afflicted with an acid-base disorder.
  • Acid-base disorders are common in chronic kidney disease and heart failure patients.
  • Chronic kidney disease (CKD) progressively impairs renal excretion of the approximately 1 mmol/kg body weight of hydrogen ions generated in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492.).
  • Metabolic acidosis resulting from the accumulation of acid (H + ) or depletion of base (HCOs-) in the body, is a common complication of patients with CKD, particularly when the glomerular filtration rate (GFR, a measure of renal function) falls below 30 ml/min/1 ,73m 2 .
  • GFR glomerular filtration rate
  • Metabolic acidosis has profound long-term effects on protein and muscle metabolism, bone turnover and the development of renal osteodystrophy.
  • metabolic acidosis may result in bone demineralization, leading to the release from the skeleton of mineral including calcium, phosphate, sodium, and potassium.
  • metabolic acidosis influences a variety of paracrine and endocrine functions, again with long-term consequences such as increased inflammatory mediators, reduced leptin, insulin resistance, and increased corticosteroid and parathyroid hormone production (Mitch WE, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.).
  • the net effect of sustained metabolic acidosis in the CKD patient is loss of bone and muscle mass, a negative nitrogen balance, and the acceleration of chronic renal failure due to hormonal and cellular abnormalities (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al, 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc.
  • CKD patients of moderate degree first develop hyperchloremic acidosis with a normal anion gap due to the inability to reclaim filtered bicarbonate and excrete proton and ammonium cations. As they progress toward the advanced stages of CKD the anion gap typically increases, reflective of the continuing degradation of the kidney’s ability to excrete the anions that were associated with the unexcreted protons.
  • the afflicted individual may have a baseline blood bicarbonate value in the normal range (i.e., in the range of 22 - 29 mEq/l) or in the acidotic range (i.e., ⁇ 22 mEq/l).
  • the baseline blood bicarbonate value may be the serum bicarbonate concentration determined at a single time point or may be the mean or median value of two or more serum bicarbonate concentrations determined at two or more time-points.
  • the baseline serum bicarbonate value may be the value of the serum bicarbonate concentration determined at a single time point and the baseline serum bicarbonate value is used as a basis to determine an acute acidic condition requiring immediate treatment.
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn at different time points (e.g., different days).
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on different days (e.g., at least 2, 3, 4, 5 or more days, that may be consecutive or separated by one or more days or even weeks).
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on two consecutive days preceding the initiation of treatment.
  • the methods described above refer to daily dose
  • a further aspect of the disclosure include the methods disclosed herein in which the dose is administered less frequently than once per day (while still being administered on a regular basis).
  • the daily dose specified may, instead, be administrated on a less frequent basis.
  • the doses disclosed here may be administered once every two or three days. In some other embodiments, the doses disclosed here may be administered once, twice or three times a week.
  • biomarkers of acid-base imbalance may be used as a measure of acid-base status.
  • blood serum or plasma
  • anion gap e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • concentration of other electrolytes e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • net acid excretion (“NAE”), urine pH, urine ammonium concentration, urine uric acid, urine oxalate, supersaturation levels of calcium oxalate (CaOx), calcium phosphate (CaP) and uric acid (UA), and/or the concentration of other electrolytes in the urine (e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate) may be used as an indicator of acid-base imbalance.
  • NAE net acid excretion
  • urine pH urine ammonium concentration
  • urine uric acid urine oxalate
  • CaP calcium phosphate
  • UA uric acid
  • concentration of other electrolytes in the urine e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • the various aspects and embodiments may have a range of advantages, such as improved or successful treatment of lithiasis disorders. Such improvements may also include reduced side effects, increased patient compliance, reduced drug loads, increased speed of treatment, increased magnitude of treatment, avoiding unwanted changes to other electrolytes and/or reduced drug-drug interactions.
  • the afflicted individual may have a baseline blood bicarbonate value of at least 22 m Eq/I .
  • the afflicted individual is afflicted with eubicarbonatemic metabolic acidosis.
  • the daily dose is no more than 100 g/day of the nonabsorbable composition.
  • the daily dose is no more than 90 g/day of the nonabsorbable composition.
  • the daily dose is no more than 75 g/day of the nonabsorbable composition.
  • the daily dose is no more than 65 g/day of the nonabsorbable composition.
  • the daily dose is no more than 50 g/day of the nonabsorbable composition.
  • the daily dose is no more than 40 g/day of the nonabsorbable composition.
  • the daily dose is no more than 30 g/day of the nonabsorbable composition.
  • the daily dose is no more than 25 g/day of the nonabsorbable composition.
  • the daily dose is no more than 20 g/day of the nonabsorbable composition.
  • the daily dose is no more than 15 g/day of the nonabsorbable composition.
  • the daily dose is no more than 10 g/day of the nonabsorbable composition.
  • the daily dose is no more than 5 g/day of the nonabsorbable composition.
  • the daily dose is no more than 3 g/day of the nonabsorbable composition.
  • the daily dose of the nonabsorbable composition has the capacity to remove at least about 5 mEq/day of the target species.
  • the daily dose of the nonabsorbable composition has the capacity to remove at least about 7.5 mEq/day, at least about 10 mEq/day, at least about 12.5 mEq/day, at least about 15 mEq/day, at least about 20 mEq/day, at least about 25 mEq/day, at least about 30 mEq/day, at least about 35 mEq/day, at least about 40 mEq/day, or at least about 50 mEq/day of the target species wherein the target species comprises protons, the conjugate base of one or more strong acids, and/or one or more strong acids.
  • the target species is hydrochloric acid.
  • the composition, nonabsorbable composition, pharmaceutical composition or crosslinked poly(allylamine) polymer of the present disclosure can comprise, or consist essentially of, or be a polymer as defined anywhere herein.
  • the composition, nonabsorbable composition, pharmaceutical composition or crosslinked poly(allylamine) polymer can comprise, or consist essentially of, or be the drug substance veverimer.
  • Nonabsorbable compositions having the medical uses described herein possess the capacity to remove clinically significant quantities of one or more target species: (i) protons, (ii) the conjugate base(s) of one or more strong acids (e.g., chloride, bisulfate (HSO4 ) and/or sulfate (SO ) ions) and/or (iii) one or more strong acids (e.g., HCI and/or H2SO4).
  • strong acids e.g., chloride, bisulfate (HSO4 ) and/or sulfate (SO ) ions
  • strong acids e.g., HCI and/or H2SO4
  • the nonabsorbable compositions may be selected from the group consisting of cation exchange compositions, anion exchange compositions, amphoteric ion exchange compositions, neutral compositions having the capacity to bind both protons and anions, composites thereof and mixtures thereof.
  • the active part of the nonabsorbable compositions may be a nonabsorbable proton binding polymer. These include all polymers disclosed in WO2014/197725 A1 and WO2016/094685 A1 .
  • the nonabsorbable composition has a preferred particle size range that is (i) large enough to avoid passive or active absorption through the Gl tract and (ii) small enough to not cause grittiness or unpleasant mouth feel when ingested as a powder, sachet and/or chewable tablet/dosage form with a mean particle size of at least 3 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 1 ,000 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 500 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 400 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 300 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 20 to 250 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 30 to 250 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 40 to 180 microns.
  • less than 7% of the particles in the population (volume distribution) have a diameter less than 10 microns.
  • less than 5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • less than 2.5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • less than 1 % of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • the particle size may be measured using the protocol set out in the abbreviations and definitions section (above).
  • a low Swelling Ratio of the nonabsorbable composition is preferred (0.5 to 10 times its own weight in water).
  • the nonabsorbable composition has a Swelling Ratio of less than 9.
  • the nonabsorbable composition has a Swelling Ratio of less than 8.
  • the nonabsorbable composition has a Swelling Ratio of less than 7.
  • the nonabsorbable composition has a Swelling Ratio of less than 6.
  • the nonabsorbable composition has a Swelling Ratio of less than 5.
  • the nonabsorbable composition has a Swelling Ratio of less than 4.
  • the nonabsorbable composition has a Swelling Ratio of less than 3.
  • the nonabsorbable composition has a Swelling Ratio of less than 2.
  • the amount of the target species (proton, conjugate base of a strong acid and/or strong acid) that is bound as the nonabsorbable composition transits the Gl tract is largely a function of the binding capacity of the composition for the target species (protons, the conjugate base of a strong acid, and/or a strong acid) and the quantity of the nonabsorbable composition administered per day as a daily dose.
  • the theoretical binding capacity for a target species may be determined using a SGF assay and determining the amount of a species that appeared in or disappeared from the SGF buffer during the SGF assay.
  • the theoretical proton binding capacity of a cation exchange resin may be determined by measuring the increase in the amount of cations (other than protons) in the buffer during a SGF assay.
  • the theoretical anion binding capacity of an anion exchange resin in a form other than the chloride form
  • the theoretical anion binding capacity of a neutral composition for protons and the conjugate base of a strong acid may be determined by measuring the decrease in chloride concentration in the buffer during a SGF assay.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 0.5 m Eq/g (as determined in an SGF assay).
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 1 mEq/g, at least about 2 mEq/g, at least about 3 mEq/g, at least about 4 mEq/g, at least about 5 mEq/g, at least about 7.5 mEq/g, at least about 10 mEq/g, at least about 12.5 mEq/g, at least about 15 mEq/g, or at least about 20 mEq/g.
  • the nonabsorbable composition will typically have a theoretical binding capacity for the target species that is not in excess of about 35 mEq/g.
  • the theoretical binding capacity of the nonabsorbable compositions for the target species may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g.
  • the binding capacities recited in this paragraph are the theoretical binding capacities for protons and the theoretical binding capacities for the conjugate base(s), independently and individually, and not the sum thereof.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay.
  • SIB Simulated Small Intestine Inorganic Buffer
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g, at least 2 mEq/g, at least 2.5 mEq/g, at least 3 mEq/g, at least 3.5 mEq/g, at least 4 mEq/g, at least 4.5 mEq/g, at least 5 mEq/g, at least 5.5 mEq/g, or at least 6 mEq/g in a SIB assay.
  • the nonabsorbable composition binds a significant amount of chloride relative to phosphate as exhibited, for example, in a SIB assay.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.25:1, respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.5:1 , at least 0.75:1 , at least 1 :1, at least 1 .25:1 , at least 1.5:1 , at least 2:1 , at least 2.5:1 , or at least 3:1 , respectively.
  • the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable cations.
  • the cation exchange material may be organic (e.g., polymeric), inorganic (e.g., a zeolite) or a composite thereof.
  • the exchangeable cations may be selected, for example, from the group consisting of lithium, sodium, potassium, calcium, magnesium, iron and combinations thereof, and more preferably from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof.
  • it is generally preferred that the nonabsorbable composition contain a combination of exchangeable cations that establish or maintain electrolyte homeostasis.
  • the nonabsorbable composition optionally contains exchangeable sodium ions, but when included, the amount of the sodium ions in a daily dose is insufficient to increase the patient’s serum sodium ion concentration to a value outside the range of 135 to 145 mEq/L
  • the nonabsorbable composition optionally contains exchangeable potassium ions, but when included, the amount of the potassium ions in a daily dose is insufficient to increase the patient’s serum potassium ion concentration to a value outside the range of 3.7 to 5.2 mEq/L.
  • the nonabsorbable composition optionally contains exchangeable magnesium ions, but when included, the amount of the magnesium ions in a daily dose is insufficient to increase the patient’s serum magnesium ion concentration to a value outside the range of 1 .7 to 2.2 mg/dL.
  • the nonabsorbable composition optionally contains exchangeable calcium ions, but when included, the amount of the calcium ions in a daily dose is insufficient to increase the patient’s serum calcium ion concentration to a value outside the range of 8.5 to 10.2 mg/dL.
  • the nonabsorbable composition contains a combination of exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof, designed to maintain serum Na + levels within the range of 135 to 145 mEq/l, serum K + levels within the range of 3.7 to 5.2 mEq/L, serum Mg 2+ levels within the range of 1 .7 to 2.2 mg/dL and serum Ca 2+ levels within the range of 8.5 to 10.2 mg/dL.
  • exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof, designed to maintain serum Na + levels within the range of 135 to 145 mEq/l, serum K + levels within the range of 3.7 to 5.2 mEq/L, serum Mg 2+ levels within the range of 1 .7 to 2.2 mg/dL and serum Ca 2+ levels within the range of 8.5 to 10.2 mg/dL.
  • the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure, optionally containing exchangeable sodium ions cations.
  • the cation exchange material may be organic (e.g., polymeric), inorganic (e.g., a molecular sieve) or a composite thereof.
  • the nonabsorbable composition contains less than 12% by weight sodium.
  • the nonabsorbable composition contains less than 9% by weight sodium.
  • the nonabsorbable composition contains less than 6% by weight sodium.
  • the nonabsorbable composition contains less than 3% by weight sodium.
  • the nonabsorbable composition contains less than 1% by weight sodium. By way of further example, in one such embodiment, the nonabsorbable composition contains less than 0.1% by weight sodium. By way of further example, in one such embodiment, the nonabsorbable composition contains less than 0.01 % by weight sodium. By way of further example, in one such embodiment, the nonabsorbable composition contains between 0.05 and 3% by weight sodium.
  • the nonabsorbable composition is a resin comprising any of a wide range of crosslinked polymeric materials that are able to bind protons in aqueous solutions.
  • exemplary crosslinked polymeric material comprises a polyanion crosslinked material selected from poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof.
  • the polyanion is coordinated to exchangeable monovalent cations, divalent cations, or a combination thereof.
  • Exemplary monovalent cations include lithium, sodium, and potassium, or any combination thereof.
  • Exemplary divalent cations include magnesium and calcium or combinations thereof.
  • the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of at least 4.
  • the polyanion backbone has an average pKa of 4-5.
  • the polyanion backbone has an average pKa of 5-6.
  • the polyanion backbone has an average pKa of 6-7.
  • the polyanion backbone has an average pKa of greater than 7.
  • Exemplary cation exchange resins include poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof.
  • these polyanion backbones are further functionalized with functional groups to affect the pKa. These functional groups can increase pKa when electron donating, or decrease pKa when electron withdrawing.
  • Exemplary electron donating groups include amino, hydroxyl, methyl ether, ether, phenyl, and amido.
  • Exemplary electron withdrawing groups include flouro, chloro, halo, sulphonyl, nitroxyl, trifluoromethyl, and cyano.
  • Further exemplary cation exchange resins include resins modified with protonable functional groups including carboxylic acids and functionalized alcohols.
  • Polymeric cation exchanger resins may be prepared using a range of chemistries, including for example, (i) substitution polymerization of polyfunctional reagents at least one of which comprises basic anionic or conjugate-acid moieties, (2) radical polymerization of a monomer comprising at least one acid or conjugate-acid containing moiety, and (3) crosslinking of a basic anionic or conjugate-acid containing intermediate with a polyfunctional crosslinker, optionally containing basic anionic or conjugate-acid moieties.
  • the resulting crosslinked polymers may thus, for example, be crosslinked homopolymers or crosslinked copolymers.
  • the resulting crosslinked polymers will typically possess repeat units comprising basic anionic or conjugate-acid, separated by the same or varying lengths of repeating linker (or intervening) units.
  • the polymers comprise repeat units comprising a basic anionic or conjugate-acid moiety and an intervening linker unit.
  • multiple basic anionic or conjugate-acid containing repeat units are separated by one or more linker units.
  • the polyfunctional crosslinkers may comprise proton binding functional groups, e.g. basic anionic, (“active crosslinkers”) or may lack proton binding functional groups such as acrylates (“passive crosslinkers”).
  • a basic anion or conjugate-acid monomer is polymerized and the polymer is concurrently crosslinked in a substitution polymerization reaction.
  • the basic anion or conjugate-acid reactant (monomer) in the concurrent polymerization and crosslinking reaction can react more than one time for the substitution polymerization.
  • the basic anion or conjugate-acid monomer is a branched basic anion or conjugate-acid possessing at least two reactive moieties to participate in the substitution polymerization reaction.
  • the nonabsorbable composition is an anion exchange material comprising at least 1 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof.
  • the nonabsorbable composition has the capacity to induce an increase in the individual’s serum bicarbonate value, at least in part, by delivering a physiologically significant amount of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent, or a combination thereof.
  • Exemplary bicarbonate equivalent anions include acetate, lactate and the conjugate bases of other short chain carboxylic acids.
  • the nonabsorbable composition comprises at least 2 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises at least 3 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises at least 4 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises at least 5 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition is an anion exchange material comprising less than 10 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof.
  • the nonabsorbable composition comprises less than 7.5 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises less than 5 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises less than 2.5 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises less than 1 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises less than 0.1 mEq/g of an anion selected from the group consisting of hydroxide, bicarbonate, carbonate, citrate or other bicarbonate equivalent anion.
  • the nonabsorbable composition comprises an amphoteric ion exchange resin.
  • amphoteric ion-exchange resins include crosslinked polystyrene, polyethylene or the like as a base material and quaternary ammonium group, carboxylic acid group and the like in (i) the same pendant groups (e.g., betaine-containing pendant groups) such as the amphoteric resin sold under the trade designation DIAION AMP03 (Mitsubishi Chemical Corporation) or (ii) different pendant groups (e.g., mixed charged copolymers containing the residues of at least two different monomers, one containing ammonium groups and one containing carboxylic acid groups), to provide a function of ion-exchanging the both of cations and negative ions.
  • DIAION AMP03 Mitsubishi Chemical Corporation
  • Exemplary amphoteric ion-exchange resins containing a mixture of cation and anion exchange sites also include resins in which a linear polymer is trapped inside a crosslinked ion exchange resin, such as the amphoteric resin sold under the trade designation DOWEXTM Retardion 11A8 (Dow Chemical Company).
  • the nonabsorbable composition comprises a neutral composition having the capacity to bind both protons and anions.
  • exemplary neutral nonabsorbable compositions that bind both protons and anions include polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, expanded porphyrins, covalent organic frameworks, and polymers containing amine and/or phosphine functional groups.
  • the nonabsorbable composition binds chloride ions
  • it is generally preferred that the nonabsorbable composition selectively bind chloride ions relative to other counter ions such as bicarbonate equivalent anions, phosphate anions, and the conjugate bases of bile and fatty acids.
  • the nonabsorbable composition (i) remove more chloride ions than bicarbonate equivalent anions (ii) remove more chloride ions than phosphate anions, and (iii) remove more chloride ions than the conjugate bases of bile and fatty acids.
  • treatment with the nonabsorbable composition does not induce or exacerbate hypophosphatemia (/.e., a serum phosphorous concentration of less than about 2.4 mg/dL, does not significantly elevate low density lipoproteins (“LDL”), or otherwise negatively impact serum or colon levels of metabolically relevant anions.
  • hypophosphatemia /.e., a serum phosphorous concentration of less than about 2.4 mg/dL
  • LDL low density lipoproteins
  • the pharmaceutical composition comprises a crosslinked polymer containing the residue of an amine corresponding to Formula 1 :
  • Ri, R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R1, R2 and R3 is other than hydrogen. Stated differently, at least one of R1, R2 and R3 is hydrocarbyl or substituted hydrocarbyl, and the others of R1, R2 and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R1, R2 and R 3 are independently hydrogen, aryl, aliphatic, heteroaryl, or heteroaliphatic provided, however, each of R1, R2 and R3 are not hydrogen.
  • R1, R2 and R3 are independently hydrogen, saturated hydrocarbons, unsaturated aliphatic, unsaturated heteroaliphatic, heteroalkyl, heterocyclic, aryl or heteroaryl, provided, however, each of R1, R2 and R 3 are not hydrogen.
  • R1, R2 and R3 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R1, R2 and Rs are not hydrogen.
  • R1, R2 and R 3 are independently hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R1, R2 and R3 are not hydrogen.
  • Ri and R2 in combination with the nitrogen atom to which they are attached together constitute part of a ring structure, so that the monomer as described by Formula 1 is a nitrogen-containing heterocycle (e.g., piperidine) and R3 is hydrogen, or heteroaliphatic.
  • R1, R2 and R3 are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R1, R2 and R3 is other than hydrogen.
  • R1, R2 and R3 are independently hydrogen, allyl, or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 wherein R1, R2, and R3 are independently hydrogen, heteroaryl, aryl, aliphatic or heteroaliphatic provided, however, at least one of R1, R2, and R3 is aryl or heteroaryl.
  • R1 and R2 in combination with the nitrogen atom to which they are attached, may form a saturated or unsaturated nitrogen-containing heterocyclic ring.
  • R1 and R2 in combination with the nitrogen atom to which they are attached may constitute part of a pyrrolidine, pyrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine, or triazine ring structure.
  • R1 and R2, in combination with the nitrogen atom to which they are attached may constitute part of a piperidine ring structure.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 wherein R1, R2, and R3 are independently hydrogen, aliphatic, or heteroaliphatic provided, however, at least one of R1, R2, and R3 is other than hydrogen.
  • R1, R2, and R3 may independently be hydrogen, alkyl, alkenyl, allyl, vinyl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, or heterocyclic provided, however, at least one of R1, R2, and Rs is other than hydrogen.
  • R1 and R2 in combination with the nitrogen atom to which they are attached may form a saturated or unsaturated nitrogen-containing heterocyclic ring.
  • R1 and R2, in combination with the nitrogen atom to which they are attached may constitute part of a pyrrolidino, pyrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, piperazine, or diazine ring structure.
  • R1 and R2, in combination with the nitrogen atom to which they are attached may constitute part of a piperidine ring structure.
  • the amine corresponding to Formula 1 is acyclic and at least one of Ri , R2, and R3 is aliphatic or heteroaliphatic.
  • R1, R2, and R3 are independently hydrogen, alkyl, allyl, vinyl, alicyclic, aminoalkyl, alkanol, or heterocyclic, provided at least one of R1, R2, and R3 is other than hydrogen.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 with a polyfunctional crosslinker (optionally also comprising amine moieties) wherein R1, R2, and R3 are independently hydrogen, alkyl, aminoalkyl, or alkanol, provided at least one of R1, R2, and R3 is other than hydrogen.
  • a polyfunctional crosslinker optionally also comprising amine moieties
  • an amine-containing monomer is polymerized and the polymer is concurrently crosslinked in a substitution polymerization reaction in the first reaction step.
  • the amine reactant (monomer) in the concurrent polymerization and crosslinking reaction can react more than one time for the substitution polymerization.
  • the amine monomer is a linear amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction.
  • the amine monomer is a branched amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction.
  • Crosslinkers for the concurrent substitution polymerization and crosslinking typically have at least two amine-reactive moieties such as alkyl-chlorides, and alkyl-epoxides.
  • primary amines react at least once and potentially may react up to three times with the crosslinker
  • secondary amines can react up to twice with the crosslinkers
  • tertiary amines can only react once with the crosslinker.
  • the formation of a significant number of quaternary nitrogens/amines is generally not preferred because quaternary amines cannot bind protons.
  • Exemplary amines that may be used in substitution polymerization reactions described herein include 1 ,3-Bis[bis(2-aminoethyl)amino]propane, 3-Amino-1- ⁇ [2-(bis ⁇ 2-[bis(3-aminopropyl)amino]ethyl ⁇ amino)ethyl](3-aminopropyl)amino ⁇ propane, 2- [Bis(2-aminoethyl)amino]ethanamine, T ris(3-aminopropyl)amine, 1 ,4-Bis[bis(3- aminopropyl)amino]butane, 1 ,2-Ethanediamine, 2-Amino-1 -(2-aminoethylamino)ethane, 1.2-Bis(2-aminoethylamino)ethane, 1 ,3-Propanediamine, 3,3'-Diaminodipropylamine,
  • crosslinking agents that may be used in substitution polymerization reactions and post-polymerization crosslinking reactions include, but are not limited to, one or more multifunctional crosslinking agents such as: dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis (halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1 ,2-epoxybutane, bromo
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 1a:
  • R4 and Rs are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
  • R4 and Rs are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, unsaturated heteroaliphatic, heterocyclic, or heteroalkyl.
  • R4 and Rs are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl.
  • R4 and Rs are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic.
  • R4 and Rs are independently hydrogen, alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, or heterocyclic.
  • R4 and Rs (in combination with the nitrogen atom to which they are attached) together constitute part of a ring structure, so that the monomer as described by Formula 1a is a nitrogen-containing heterocycle (e.g., piperidine).
  • R4 and Rs are independently hydrogen, aliphatic or heteroaliphatic.
  • R4 and Rs are independently hydrogen, allyl, or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 1b and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1b with a polyfunctional crosslinker (optionally also comprising amine moieties):
  • R4 and Rs are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, Re is aliphatic and Rei and R62 are independently hydrogen, aliphatic, or heteroaliphatic.
  • R4 and Rs are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic.
  • R4 and Rs are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl.
  • R 4 and Rs are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic.
  • R4 and Rs are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic.
  • R4 and Rs (in combination with the nitrogen atom to which they are attached) together constitute part of a ring structure, so that the monomer as described by Formula 1a is a nitrogen-containing heterocycle (e.g., piperidine).
  • R4 and Rs are independently hydrogen, aliphatic or heteroaliphatic.
  • R4 and Rs are independently hydrogen, allyl, or aminoalkyl.
  • Re may be methylene, ethylene or propylene
  • Rei and R62 may independently be hydrogen, allyl or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2:
  • R10, R20, R30, and R40 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl
  • X2 is hydrocarbyl or substituted hydrocarbyl; each X11 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; and z is a non-negative number.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m and n are independently 0, 1 , 2 or 3 and n is 0 or 1.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2
  • the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2
  • R10, R20, R30, and R40 are independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl.
  • Rio, R20, R30, and R40 are independently hydrogen, aliphatic, or heteroaliphatic.
  • R10, R20, R30, and R40 are independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl.
  • R10, R20, R30, and 40 are independently hydrogen, alkyl, allyl, vinyl, -(CH2)dNH2, -(CH2)dN[(CH2)eNH2)]2 where d and e are independently 2-4.
  • m and z may independently be 0, 1 , 2 or 3 and n is 0 or 1 .
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and X2 is aliphatic or heteroaliphatic.
  • X2 is aliphatic or heteroaliphatic and R10, R20, R30, and R40 are independently hydrogen, aliphatic, heteroaliphatic.
  • X2 is alkyl or aminoalkyl and R10, R20, R30, and 40 are independently hydrogen, aliphatic, or heteroaliphatic.
  • m and z may independently be 0, 1 , 2 or 3 and n is 0 or 1 .
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m is a positive integer.
  • m is a positive integer
  • z is zero
  • R20 is hydrogen, aliphatic or heteroaliphatic.
  • m is a positive integer (e.g., 1 to 3)
  • z is a positive integer (e.g., 1 to 2)
  • Xu is hydrogen, aliphatic or heteroaliphatic
  • R20 is hydrogen, aliphatic or heteroaliphatic.
  • m is a positive integer
  • z is zero, one or two
  • X11 is hydrogen alkyl, alkenyl, or aminoalkyl
  • R20 is hydrogen, alkyl, alkenyl, or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and n is a positive integer and R30 is hydrogen, aliphatic or heteroaliphatic.
  • n is 0 or 1
  • R30 is hydrogen, alkyl, alkenyl, or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m and n are independently non-negative integers and X2 is aliphatic or heteroaliphatic.
  • m is 0 to 2
  • n is 0 or 1
  • X2 is aliphatic or heteroaliphatic
  • R10, R20, R30, and R40 are independently hydrogen, aliphatic, or heteroaliphatic.
  • m is 0 to 2
  • n is 0 or 1
  • X2 is alkyl or aminoalkyl
  • R10, R20, R30, and R40 are independently hydrogen, aliphatic, or heteroaliphatic.
  • m is 0 to 2
  • n is 0 or 1
  • X2 is alkyl or aminoalkyl
  • R10, R20, R30, and R40 are independently hydrogen, alkyl, alkenyl, or aminoalkyl.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 2a with a polyfunctional crosslinker (optionally also comprising amine moieties):
  • Formula 2a wherein m and n are independently non-negative integers; each R11 is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;
  • R21 and R31 are independently hydrogen or heteroaliphatic
  • R41 is hydrogen, substituted hydrocarbyl, or hydrocarbyl
  • X2 is alkyl or substituted hydrocarbyl; each X12 is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and z is a non-negative number.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a
  • the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 with a polyfunctional crosslinker (optionally also comprising amine moieties).
  • a polyfunctional crosslinker optionally also comprising amine moieties.
  • m and z are independently 0, 1 , 2 or 3, and n is 0 or 1 .
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a
  • the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 2a with a polyfunctional crosslinker (optionally also comprising amine moieties)
  • each Rn is independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl
  • R21 and R31 are independently hydrogen or heteroaliphatic
  • R41 is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl.
  • each Rn is hydrogen, aliphatic, aminoalkyl, or haloalkyl
  • R21 and R31 are independently hydrogen or heteroaliphatic
  • R41 is hydrogen, alkylamino, aminoalkyl, aliphatic, or heteroaliphatic.
  • each Rn is hydrogen, aliphatic, aminoalkyl, or haloalkyl
  • R21 and R31 are hydrogen or aminoalkyl
  • R41 is hydrogen, aliphatic, or heteroaliphatic.
  • each R11 and R41 is independently hydrogen, alkyl, or aminoalkyl
  • R21 and R31 are independently hydrogen or heteroaliphatic.
  • each R11 and R41 is independently hydrogen, alkyl, -(CH2)dNH2, - (CH 2 )dN[(CH2)eNH 2 )]2 where d and e are independently 2-4, and R21 and R31 are independently hydrogen or heteroaliphatic.
  • m and z may independently be 0, 1 , 2 or 3, and n is 0 or 1 .
  • Exemplary amines for the synthesis of polymers comprising repeat units corresponding to Formula 2a include, but are not limited to, amines appearing in Table A.
  • Exemplary crosslinkers for the synthesis of polymers comprising the residue of amines corresponding to Formula 2a include but are not limited to crosslinkers appearing in Table B.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b and the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b:
  • Formula 2b wherein m and n are independently non-negative integers; each R12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;
  • R22 and R32 are independently hydrogen substituted hydrocarbyl, or hydrocarbyl
  • R42 is hydrogen, hydrocarbyl or substituted hydrocarbyl
  • X2 is alkyl, aminoalkyl, or alkanol; each X13 is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; z is a non-negative number, and the amine corresponding to Formula 2b comprises at least one allyl group.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b
  • the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b
  • m and z are independently 0, 1 , 2 or 3
  • n is 0 or 1.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b, the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 1 , and (i) R12 or R42 independently comprise at least one allyl or vinyl moiety, (ii) m is a positive integer and R22 comprises at least one allyl or vinyl moiety, and/or (iii) n is a positive integer and R32 comprises at least one allyl moiety.
  • m and z are independently 0, 1 , 2 or 3 and n is 0 or 1 .
  • R12 or R42 in combination comprise at least two allyl or vinyl moieties.
  • m is a positive integer and R12, R22 and R42, in combination comprise at least two allyl or vinyl moieties.
  • n is a positive integer and R12, R32 and R42, in combination comprise at least two allyl or vinyl moieties.
  • m is a positive integer
  • n is a positive integer and R12, R22, R32 and R42, in combination, comprise at least two allyl or vinyl moieties.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b
  • the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b
  • each R12 is independently hydrogen, aminoalkyl, allyl, or vinyl
  • R22 and R32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic heterocyclic, or aryl
  • R42 is hydrogen or substituted hydrocarbyl.
  • each Ri2 is aminoalkyl, allyl or vinyl
  • R22 and R32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, or alkanol
  • R42 is hydrogen or substituted hydrocarbyl.
  • each Ri2 and R42 is independently hydrogen, alkyl, allyl, vinyl, -(CH2)dNH2 or -(CH2)dN[(CH2)eNH2]2 where d and e are independently 2-4, and R22 and R32 are independently hydrogen or heteroaliphatic.
  • Exemplary amines and crosslinkers (or the salts thereof, for example the hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromic acid salts thereof) for the synthesis of polymers described by Formula 2b include but are not limited to the ones in Table C. Table C
  • the crosslinked polymer is derived from a reaction of the resulting polymers that utilize monomers described in any of Formulae 1 , 1 a, 1 b, 1 c, 2, 2a and 2b or a linear polymer comprised of a repeat unit described by Formula 3 with external crosslinkers or pre-existing polymer functionality that can serve as crosslinking sites.
  • Formula 3 can be a repeat unit of a copolymer or terpolymer where X15 is either a random, alternating, or block copolymer.
  • the repeating unit in Formula 3 can also represent the repeating unit of a polymer that is branched, or hyperbranched, wherein the primary branch point can be from any atom in the main chain of the polymer:
  • R15, R16 and R17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo;
  • X5 is hydrocarbyl, substituted hydrocarbyl, oxo (-O-), or amino and z is a non-negative number.
  • R15, R16 and R17 are independently hydrogen, aryl, or heteroaryl
  • X5 is hydrocarbyl, substituted hydrocarbyl, oxo or amino
  • m and z are nonnegative integers.
  • R15, R16 and R17 are independently aliphatic or heteroaliphatic
  • X5 is hydrocarbyl, substituted hydrocarbyl, oxo (-O-) or amino
  • m and z are non-negative integers.
  • R15, Ri6 and R17 are independently unsaturated aliphatic or unsaturated heteroaliphatic, Xs is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer.
  • Ris, Rie and R17 are independently alkyl or heteroalkyl, Xs is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer.
  • Ris, Rie and R17 are independently alkylamino, aminoalkyl, hydroxyl, amino, boronic acid, halo, haloalkyl, alkanol, or ethereal, Xs is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer.
  • Ris, Rie and R17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo, Xs is oxo, amino, alkylamino, ethereal, alkanol, or haloalkyl, and z is a non- negative integer.
  • Exemplary crosslinking agents that may be used in radical polymerization reactions include, but are not limited to, one or more multifunctional crosslinking agents such as: 1 ,4-bis(allylamino)butane, 1 ,2-bis(allylamino)ethane, 2-(allylamino)-1-[2- (allylamino)ethylamino]ethane, 1 ,3-bis(allylamino)propane, 1 ,3-bis(allylamino)-2-propanol, triallylamine, diallylamine, divinylbenzene, 1 ,7-octadiene, 1 ,6-heptadiene, 1 ,8-nonadiene, 1 ,9-decadiene, 1 ,4-divinyloxybutane, 1 ,6-hexamethylenebisacrylamide, ethylene bisacrylamide, N,N'-bis(vinylsulfonylacetyl)ethylene diamine, 1 ,
  • Crosslinked polymers derived from the monomers and polymers in formulas 1 through 3 may be synthesized either in solution or bulk or in dispersed media.
  • solvents that are suitable for the synthesis of polymers of the present disclosure include, but are not limited to water, low boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethylsulfoxide, heptane, chlorobenzene, toluene.
  • Alternative polymer processes may include, a lone polymerization reaction, stepwise addition of individual starting material monomers via a series of reactions, the stepwise addition of blocks of monomers, combinations or any other method of polymerization such as living polymerization, direct polymerization, indirect polymerization, condensation, radical, emulsion, precipitation approaches, spray dry
  • Processes can be carried out as a batch, semi-continuous and continuous processes.
  • the continuous phase can be non-polar solvents, such as toluene, benzene, hydrocarbon, halogenated solvents, and super critical carbon dioxide.
  • water can be used and salt can be used to tune the properties of the suspension.
  • the starting molecules described in formulas 1 through 3 may be copolymerized with one or more other monomers of the invention, oligomers or other polymerizable groups.
  • Such copolymer architectures can include, but are not limited to, block or block-like polymers, graft copolymers, and random copolymers.
  • Incorporation of monomers described by formulas 1 through 3 can range from 1 % to 99%. In some embodiments, the incorporation of comonomer is between 20% and 80%.
  • Non-limiting examples of comonomers which may be used alone or in combination include: styrene, allylamine hydrochloride, substituted allylamine hydrochloride, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N,N-dialkylacrylamide, N,N- dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinyl amide, maleic acid derivatives, vinyl ether, allyle, methallyl monomers and combinations thereof.
  • Additional specific monomers or comonomers that may be used in this invention include, but are not limited to, 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2- aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, amethylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, 2-propen-1-ylamine,
  • Additional modification to the preformed crosslinked polymer can be achieved through the addition of modifiers, including but not limited to amine monomers, additional crosslinkers, and polymers. Modification can be accomplished through covalent or non-covalent methods. These modifications can be evenly or unevenly dispersed throughout the preformed polymer material, including modifications biased to the surface of the preformed crosslinked polymer. Furthermore, modifications can be made to change the physical properties of the preformed crosslinked polymer, including but not limited to reactions that occur with remaining reactive groups such as haloalkyl groups and allyl groups in the preformed polymer. Reactions and modifications to the preformed crosslinked polymer can include but are not limited to acid-base reactions, nucleophilic
  • the post-polymerization crosslinked amine polymer is a crosslinked amine polymer comprising a structure corresponding to Formula 4: wherein each R is indendently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer ( N ) and a, b, c, and m are integers.
  • m is a large integer indicating an extended polymer network.
  • a ratio of the sum of a and b to c is in the range of about 1 :1 to 5:1 .
  • a ratio of the sum of a and b to c is in the range of about 1.5:1 to 4:1.
  • a ratio of the sum of a and b to c is in the range of about 1 .75:1 to 3:1 .
  • a ratio of the sum of a and b is 57, c is 24 and m is large integer indicating an extended polymer network.
  • a ratio of the sum of a and b to c may be in the range of about 2:1 to 2.5:1. .
  • the pharmaceutical composition comprises veverimer, a polymeric drug that can have the following structural properties:
  • Veverimer can be poly(allylamine-co-N,N'-diallyl-1 ,3-diaminopropane-co- 1 ,2-diaminoethane).
  • veverimer can be a poly[(A/ 1 ,/V 3 -di(prop-2-en-1- yl)propane-1 ,3-diamine)-co-prop-2-en-1 -amine], crosslinked with A/,A/-ethane-1 ,2-diyl bridges (the mole ratio is » 2:5:2 (i.e. it is about 2 : about 5: about 2 of A/ 1 ,A/ 3 -di(prop-2-en- 1 -yl)propane-1 ,3-diamine : prop-2-en-1 -amine : N, A/'-ethane-1 ,2-diyl bridges)) polymer.
  • Veverimer can comprise the following amounts of residues of monomers: a) 20-25 mol% residue of N,N’-diallyl-1 ,3-diaminopropane, or a salt thereof, (also called 1 ,3-bis(allylamino)propane, or a salt thereof), b) 50-60 mol% residue of 2-propen-1 -ylamine, or a salt thereof, and c) 20-25 mol% residue of 1 ,2-dichloroethane, wherein the total mol% of the residues is not greater than 100 mol%.
  • Veverimer can have a carbon to nitrogen weight ratio in the range of about 3.7:1 to about 3.8:1 , respectively.
  • the carbon to nitrogen weight ratio may be determined by elemental analysis.
  • the carbon to nitrogen weight ratio may be determined by elemental analysis using a Perkin-Elmer 2400 Elemental Analyzer as more fully described elsewhere herein.
  • Veverimer can be a nonabsorbable composition that is insoluble, e.g. under physiological conditions.
  • Veverimer can have a median particle size of greater than 1 micrometer and less than 1 millimeter.
  • the particle size of veverimer may be measured by wet laser diffraction using Mie theory.
  • Veverimer may be prepared as follows:
  • Veverimer is obtainable by first copolymerizing 2-propen-1-ylamine, or a salt thereof, and 1 ,3-bis(allylamino)propane, or a salt thereof, to form a poly(allylamine) polymer, followed by crosslinking the poly(allylamine) polymer with 1 ,2-dichloroethane.
  • veverimer is obtainable by first copolymerizing 2-propen-1- ylamine hydrochloride and 1 ,3-bis(allylamino)propane dihydrochloride to form a poly(allylamine) polymer, followed by crosslinking the poly(allylamine) polymer with 1 ,2- dichloroethane.
  • the pharmaceutical composition comprises a mixture of any of the previously-identified nonabsorbable materials.
  • the pharmaceutical composition comprises a mixture of a cation exchange composition with at least one anion exchange composition, amphoteric ion exchange composition, or neutral composition having the capacity to bind both protons and anions.
  • the pharmaceutical composition comprises a mixture of an anion exchange composition with at least one cation exchange composition, amphoteric ion exchange composition, or neutral composition having the capacity to bind both protons and anions.
  • the pharmaceutical composition comprises a mixture of a neutral composition having the capacity to bind both protons and anions with at least one cation exchange composition, amphoteric ion exchange composition, or anion exchange composition.
  • the dosage levels of the nonabsorbable compositions for therapeutic and/or prophylactic uses may range from about 0.1 g/day to about 100 g/day.
  • the dose be in the range of about 0.1 g/day to about 50 g/day.
  • the dose will be about 0.5 g/day to about 25 g/day.
  • the dose will be about 1 g/day to about 25 g/day.
  • the dose will be about 4 g/day to about 25 g/day.
  • the dose will be about 5 g/day to about 25 g/day.
  • the dose will be about 2.5 g/day to about 20 g/day.
  • the dose will be about 2.5 g/day to about 15 g/day.
  • the dose will be about 1 g/day to about 10 g/day.
  • the daily dose may be administered as a single dose (/.e., one time a day), or divided into multiple doses (e.g., two, three or more doses) over the course of a day.
  • the nonabsorbable compositions may be administered as a fixed daily dose or titrated. The titration may occur at the onset of treatment or throughout, as required, and starting and maintenance dosage levels may differ from patient to patient based on severity of the underlying disease.
  • the effectiveness of the nonabsorbable composition may be established in animal models, or in human volunteers and patients.
  • in vitro, ex vivo and in vivo approaches are useful to establish HCI binding.
  • In vitro binding solutions can be used to measure the binding capacity for proton, chloride and other ions at different pHs.
  • Ex vivo extracts, such as the gastrointestinal lumen contents from human volunteers or from model animals can be used for similar purposes. The selectivity of binding and/or retaining certain ions preferentially over others can also be demonstrated in such in vitro and ex vivo solutions.
  • the nonabsorbable compositions are provided (by oral administration) to an animal, including a human, in a dosing regimen of one, two or even multiple (/.e., at least three) doses per day to treat a lithiasis disorder.
  • a daily dose of the nonabsorbable composition (whether orally administered in a single dose or multiple doses over the course of the day) has sufficient capacity to remove at least 5 mmol of protons, chloride ions or each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 10 mmol of protons, chloride ions or each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 20 mmol of protons, the conjugate base of a strong acid (e.g., Cl’, HSO and SC 2 ') and/or a strong acid (e.g., HCI or H2SO4) each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 30 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 40 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 50 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • the dosage unit form of the pharmaceutical comprising the nonabsorbable composition may be any form appropriate for oral administration. Such dosage unit forms include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, and the like.
  • the pharmaceutical composition comprises only the nonabsorbable composition.
  • the pharmaceutical composition may comprise a carrier, a diluent, or excipient in addition to the nonabsorbable composition.
  • Examples of carriers, excipients, and diluents that may be used in these formulations as well as others include foods, drinks, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, propylhydroxybenzoates, and talc.
  • compositions further include a binder, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as magnesium stearate, stearic acid, sodium stearyl fumurate and vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate.
  • a binder such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum
  • a flavoring agent such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol
  • additives may include plasticizers, pigments, talc, and the like.
  • plasticizers pigments, talc, and the like.
  • suitable ingredients are well-known in the art; see, e.g., Gennaro A R (ed), Remington's Pharmaceutical Sciences, 20th Edition.
  • the nonabsorbable composition may be coadministered with other active pharmaceutical agents depending on the condition being treated. This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
  • the non-absorbable composition may be co-administered with phosphate binders, sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, calcimimetics, sodium thiosulfate, antibiotics, urease inhibitors, thiol-containing drugs (e.g., tiopronin and D-penicillamine), allopurinol, thiazide diuretics or febuxostat.
  • the nonabsorbable composition may be co-administered with common treatments that are required to treat underlying comorbidities including but not limited to edema, hypertension, diabetes, obesity, heart failure and complications of Chronic Kidney Disease.
  • these medications and the nonabsorbable composition can be formulated together in the same dosage form and administered simultaneously as long as they do not display any clinically significant drug-drug-interactions.
  • these treatments and the nonabsorbable composition may be separately and sequentially administered with the administration of one being followed by the administration of the other.
  • the daily dose is compliance enhancing (approximately 15 g or less per day) and optionally achieves a clinically significant and sustained increase of serum bicarbonate of approximately 3 mEq/L at these daily doses.
  • Embodiment 1 A nonabsorbable composition for use in the medical treatment of a lithiasis disorder wherein the medical treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 2 A method of treating a lithiasis disorder wherein the treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment s A nonabsorbable composition for use in the medical treatment of a lithiasis disorder in a subject afflicted with chronic kidney disease (“CKD”) wherein the medical treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • CKD chronic kidney disease
  • Embodiment 4 A method of treating a lithiasis disorder in a subject afflicted with chronic kidney disease (“CKD”) wherein the treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • CKD chronic kidney disease
  • Embodiment s A nonabsorbable composition for use in the medical treatment of a lithiasis disorder in a subject afflicted with metabolic acidosis wherein the medical treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • Embodiment 6 A nonabsorbable composition for use in the medical treatment of a lithiasis disorder in a subject afflicted with eubicarbonatemic acidosis wherein the medical treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • a nonabsorbable composition for use in the medical treatment of a lithiasis disorder in a subject afflicted with eubicarbonatemic acidosis wherein the medical treatment comprises orally administering a nonabsorbable composition and the nonabsorbable composition comprises veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • Embodiment 8 A method of treating a lithiasis disorder in a subject afflicted with metabolic acidosis wherein the treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • Embodiment 9 A method of treating a lithiasis disorder in a subject afflicted with eubicarbonatemic acidosis wherein the treatment comprises orally administering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of the subject.
  • Embodiment 10 A method of treating a lithiasis disorder in a subject afflicted with eubicarbonatemic acidosis wherein the treatment comprises orally administering a nonabsorbable composition, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • a nonabsorbable composition a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • Embodiment 11 A nonabsorbable composition for use in the medical treatment of a lithiasis disorder wherein the medical treatment comprises orally administering the nonabsorbable composition and the nonabsorbable composition comprises a crosslinked poly(allylamine) polymer.
  • Embodiment 12 A method of treating a lithiasis disorder wherein the treatment comprises orally administering a nonabsorbable composition comprising a crosslinked poly(allylamine) polymer.
  • a nonabsorbable composition for use in the medical treatment of a lithiasis disorder wherein the medical treatment comprises orally administering the nonabsorbable composition and the nonabsorbable composition is veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1- ylamine, or a salt thereof, 1,3-bis(allylamino)propane, or a salt thereof, and
  • Embodiment 14 A method of treating a lithiasis disorder wherein the medical treatment comprises orally administering veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof,
  • Embodiment 15 A nonabsorbable composition for use in the medical treatment of a lithiasis disorder wherein the medical treatment comprises orally administering the nonabsorbable composition and the nonadsorbable composition comprises a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1- ylamine, or a salt thereof, 1,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • Embodiment 16 A method of treating a lithiasis disorder wherein the treatment comprises orally administering a nonabsorbable composition and the nonadsorbable composition comprises a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • a nonabsorbable composition for use in the medical treatment of a disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the medical treatment comprises orally admininstering the nonabsorbable composition and the nonabsorbable composition has the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 18 A method of treating a disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the treatment comprises orally admininstering a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 20 A method of treating a disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the method comprises orally administering a nonadsorbable composition comprising a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof,
  • Embodiment 21 A nonabsorbable composition for use in the medical treatment of a disorder associated with the formation of a crystalline mineral in an organ or tissue and the medical treatment comprises orally administering veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof,
  • Embodiment 22 A method of treating a disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the method comprises orally administering veverimer, a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1-ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • a nonabsorbable composition for use in the medical treatment of a disorder associated with the formation of a crystalline mineral in an organ or tissue and the medical treatment comprises orally administering a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 24 A method of treating a disorder associated with the formation of a crystalline mineral in an organ or tissue wherein the method comprises orally administering a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 25 A composition for use in a method of treating an individual afflicted with a lithiasis disorder, the method comprising oral administration of a nonabsorbable composition, wherein the nonabsorbable composition given orally binds at least 5 mEq per day on average of a target species in the digestive system, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 26 A method of treating a lithiasis disorder in an afflicted individual, the method comprising oral administration of a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 27 A composition for use in a method of treating a lithiasis disorder in an afflicted individual, the composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 28 A method of treating a lithiasis disorder in an afflicted individual, the method comprising orally administering a nonabsorbable composition having the capacity to increase the individual’s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, said nonabsorbable composition having the capacity to bind a target species as it transits the digestive system, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 29 A composition for use in a method of treating a lithiasis disorder in an afflicted individual, the method comprising orally administering a nonabsorbable composition having the capacity to increase the individual’s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, said nonabsorbable composition having the capacity to bind a target species as it transits the digestive system, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 30 A method of treating a lithiasis disorder in an afflicted individual having a blood bicarbonate value of at least 22 mEq/l, the method comprising orally administering a nonabsorbable composition having the capacity to bind a target species as it transits the digestive system, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 31 A composition for use in a method of treating a lithiasis disorder in an afflicted individual, the method comprising orally administering a nonabsorbable composition having the capacity to bind a target species as it transits the digestive system, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 32 The method or composition for use of any previous enumerated embodiment wherein the lithiasis order is calciphylaxis, vascular calcification, tumor lysis syndrome, kidney or bladder stones (e.g. calcium oxalate, calcium phosphate, calcium citrate, uric acid, cystine, struvite).
  • the lithiasis order is calciphylaxis, vascular calcification, tumor lysis syndrome, kidney or bladder stones (e.g. calcium oxalate, calcium phosphate, calcium citrate, uric acid, cystine, struvite).
  • Embodiment 33 The method or composition for use of any previous enumerated embodiment wherein the oral administration is as frequent as at least weekly within a treatment period.
  • Embodiment 34 The method or composition for use of any previous enumerated embodiment wherein the oral administration is as frequent as at least semiweekly within a treatment period.
  • Embodiment 35 The method or composition for use of any previous enumerated embodiment wherein the oral administration is as frequent as at least daily within a treatment period.
  • Embodiment 36 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of less than 29 mEq/L
  • Embodiment 37 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 15 mEq/L
  • Embodiment 38 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 16 mEq/L
  • Embodiment 39 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 17 mEq/L
  • Embodiment 40 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 18 mEq/L
  • Embodiment 41 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 19 mEq/L
  • Embodiment 42 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 20 mEq/L
  • Embodiment 43 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 21 mEq/L
  • Embodiment 44 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 22 mEq/L
  • Embodiment 45 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 23 mEq/L
  • Embodiment 46 The method or composition for use of any previous enumerated embodiment wherein the afflicted individual has a baseline serum bicarbonate value of at least 24 mEq/L
  • Embodiment 47 The method or composition for use of any preceding enumerated embodiment wherein the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point.
  • Embodiment 48 The method or composition for use of any preceding enumerated embodiment wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations determined at different time-points.
  • Embodiment 49 The method or composition for use of any preceding enumerated embodiment wherein the baseline serum bicarbonate value is the mean or median value of at least two serum bicarbonate concentrations for serum samples drawn on non-consecutive days.
  • Embodiment 50 The method or composition for use of any preceding enumerated embodiment wherein the non-consecutive days are separated by at least two days.
  • Embodiment 51 The method or composition for use of any preceding enumerated embodiment wherein the non-consecutive days are separated by at least one week.
  • Embodiment 52 The method or composition for use of any preceding enumerated embodiment wherein the afflicted individual is also afflicted with metabolic acidosis.
  • Embodiment 53 The method or composition for use of any preceding enumerated embodiment wherein the afflicted individual is also afflicted with eubicarbonatemic metabolic acidosis.
  • Embodiment 54 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the capacity to remove at least 5 mEq of the target species as it transits the digestive system.
  • Embodiment 55 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the
  • Embodiment 56 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the capacity to remove at least 10 mEq of the target species as it transits the digestive system.
  • Embodiment 57 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the capacity to remove at least 15 mEq of the target species as it transits the digestive system.
  • Embodiment 58 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the capacity to remove at least 20 mEq of the target species as it transits the digestive system.
  • Embodiment 59 The method or composition for use of any preceding enumerated embodiment wherein a daily dose of the nonabsorbable composition has the capacity to remove at least 25 mEq of the target species as it transits the digestive system.
  • Embodiment 60 The method or composition for use of any preceding enumerated embodiment wherein the daily dose is no more than 25 g/day.
  • Embodiment 61 The method or composition for use of any preceding enumerated embodiment wherein the daily dose is no more than 20 g/day.
  • Embodiment 62 The method or composition for use of any preceding enumerated embodiment wherein the daily dose is no more than 15 g/day.
  • Embodiment 63 The method or composition for use of any preceding enumerated embodiment wherein the daily dose is no more than 10 g/day.
  • Embodiment 64 The method or composition for use of any preceding enumerated embodiment wherein the daily dose is no more than 5 g/day.
  • Embodiment 65 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a median particle diameter size (volume distribution) in the range of 5 to 500 microns.
  • Embodiment 66 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population
  • Embodiment 67 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a median particle diameter size (volume distribution) in the range of 40 to 180 microns.
  • Embodiment 68 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a median particle diameter size (volume distribution) in which less than 5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • Embodiment 69 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a median particle diameter size (volume distribution) in which less than 1 % of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • Embodiment 70 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a Swelling Ratio of less than 3.
  • Embodiment 71 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a population of particles having a Swelling Ratio of less than 2.
  • Embodiment 72 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 5 mEq/g.
  • Embodiment 73 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 7.5 mEq/g.
  • Embodiment 74 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 10 mEq/g.
  • Embodiment 75 The method or composition for use of any preceding enumerated embodiment wherein the theoretical binding capacity for the target species is the theoretical binding capacity as determined in a SGF assay.
  • Embodiment 76 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises protons.
  • Embodiment 77 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid.
  • Embodiment 78 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid selected from the group consisting of chloride, bisulfate and sulfate ions.
  • Embodiment 79 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises chloride ions.
  • Embodiment 80 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises a strong acid.
  • Embodiment 81 The method or composition for use of any preceding enumerated embodiment wherein the target species comprises hydrochloric acid.
  • Embodiment 82 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay.
  • Embodiment 83 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
  • Embodiment 84 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay.
  • Embodiment 85 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay.
  • Embodiment 86 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a
  • Embodiment 87 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.5:1 , respectively.
  • Embodiment 88 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.75:1 , respectively.
  • Embodiment 89 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1 :1 , respectively.
  • Embodiment 90 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.5:1 , respectively.
  • Embodiment 91 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2:1 , respectively.
  • Embodiment 92 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable cations.
  • Embodiment 93 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions.
  • Embodiment 94 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material
  • the nonabsorbable composition 75 having the capacity to bind protons in aqueous solutions and the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone.
  • Embodiment 95 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions and the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone wherein the polyanion backbone is selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof.
  • the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions and the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone wherein the polyanion backbone is selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly
  • Embodiment 96 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material.
  • Embodiment 97 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material is microporous or mesoporous.
  • Embodiment 98 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a molecular sieve.
  • Embodiment 99 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a molecular sieve selected from the group consisting of silicas, metalloaluminates, aluminophosphates and gallogerminates.
  • Embodiment 100 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a silica molecular sieve.
  • Embodiment 101 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a titanoslicate molecular sieve.
  • Embodiment 102 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a zeolite, a borosilicate, a gallosilicate, a ferrisilicate or a chromosilicate molecular sieve.
  • Embodiment 103 The method of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a ceramic material and the ceramic material comprises a molecular sieve.
  • Embodiment 104 The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions.
  • Embodiment 105 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions and the anion exchange material is organic, inorganic, or a composite thereof.
  • the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions and the anion exchange material is organic, inorganic, or a composite thereof.
  • Embodiment 106 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1 :
  • Ri, R2 and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R1, R2 and R3 is other than hydrogen.
  • Embodiment 107 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a protonbinding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1 :
  • Ri, R2 and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R1, R2 and R3 is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C, and (ii) an equilibrium swelling ratio in deionized water of about 2 or less.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 108 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises the residue of an amine corresponding to Formula 1 :
  • R1, R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R1, R2 and R3 is other than hydrogen
  • the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less
  • the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1 , respectively, in an interfering ion buffer at 37 °C wherein the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36mM chloride and 20mM phosphate.
  • Embodiment 109 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 110 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 111 The method or composition for use of any preceding enumerated embodiment wherein Ri, R2 and Rs are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R1, R2 and R3 is not hydrogen.
  • Embodiment 112. The method or composition for use of any preceding enumerated embodiment wherein R1, R2 and R3 are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R1, R2 and R3 is other than hydrogen.
  • Embodiment 113 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a crosslinked amine polymer prepared by substitution polymerization of the amine with a polyfunctional crosslinker, optionally also comprising amine moieties.
  • Embodiment 114 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1a and prepared by radical polymerization of an amine corresponding to Formula 1a:
  • R4 and Rs are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
  • Embodiment 115 The method or composition for use of any preceding enumerated embodiment wherein R4 and Rs are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic.
  • Embodiment 116 The method or composition for use of any preceding enumerated embodiment wherein R4 and Rs are independently hydrogen, aliphatic or heteroaliphatic.
  • Embodiment 117 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition comprises a crosslinked amine polymer containing the residue of an amine corresponding to Formula 1 b and the crosslinked amine polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 b with a polyfunctional crosslinker:
  • Embodiment 118 The method or composition for use of any preceding enumerated embodiment wherein R4 and Rs are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic.
  • Embodiment 119 The method or composition for use of any preceding enumerated embodiment wherein R4 and Rs are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic.
  • Embodiment 120 The method or composition for use of any preceding enumerated embodiment wherein R4 and Rs are independently hydrogen, allyl, or aminoalkyl.
  • Embodiment 121 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1 -ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1 -ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • Embodiment 122 The method or composition for use of any preceding enumerated embodiment wherein the nonabsorbable composition is veverimer.
  • Embodiment 123 A nonabsorbable composition for use in a method of treatment of an individual afflicted with a lithiasis disorder, wherein the method comprises oral administration of the nonabsorbable composition and the nonabsorbable composition has the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 124 Embodiment 124.
  • a method of treatment of an individual afflicted with a lithiasis disorder comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 125 A method of reducing lithiasis-related inpatient hospitalization rates, the method comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 126 A method of reducing kidney stone-related inpatient hospitalization rates, the method comprising oral administration of a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system of a subject.
  • Embodiment 127 The nonabsorbable composition of enumerated embodiment 123 or the method of any one of enumerated embodiments 124-126, wherein the target species is hydrochloric acid.
  • Embodiment 128 The nonabsorbable composition of enumerated embodiment 123 or the method of any one of enumerated embodiments 124-126, wherein the nonabsorbable composition is a crosslinked poly(allyamine) polymer comprising the residues of 2-propen-1 -ylamine, or a salt thereof, 1 ,3-bis(allylamino)propane, or a salt thereof, and 1 ,2-dichloroethane.
  • Embodiment 129 The nonabsorbable composition of enumerated embodiment 123 or the method of any one of enumerated embodiments 124-126, wherein the nonabsorbable composition is veverimer.
  • Kidney stones affect approximately 9-11% of the American adult population (Singh et al. 2022; Ferraro et al. 2022; Chewcharat and Curhan, 2021). Most kidney stones contain calcium, usually in the form of calcium oxalate or calcium phosphate alone or in combination. Less commonly, kidney stones may be composed of uric acid, struvite, or cysteine (Singh et al. 2015). While kidney stones may be asymptomatic, stone passage through the collecting system is often painful and may require urologic intervention (Miano et al. 2007).
  • kidney disease is a major public health problem with an estimated global prevalence of between 11 to 13% (Scales et al. 2012). Both kidney stones and CKD share common risk factors such as diabetes, metabolic syndrome, and
  • Metabolic acidosis characterized by retention of acid or loss of bicarbonate, is associated with a reduction of serum bicarbonate (Wesson et al. 2020).
  • metabolic acidosis is associated with enhanced ammonia production but impaired ammonium excretion which might lead to an acidic urinary pH (Han, 2011 ) which favor the formation of uric acid stones (Wagner and Mohebbi, 2010; Adomako and Moe, 2020).
  • metabolic acidosis can also be associated with increased urinary calcium excretion through release of bone calcium (Bushinsky and Krieger, 2022) and changes in calcium transport within the kidney tubule (Alexander et al.
  • the data extract was first queried to identify individuals with non-dialysis CKD Stages G3-G5, established by 2 consecutive eGFR values >10 and ⁇ 60 mL/min/1 ,73m 2 , 90-365 days apart. Starting on or after the second eGFR test establishing CKD, study cohort inclusion further required 2 consecutive serum bicarbonate values 28- 365 days apart, both either 12 to ⁇ 22 mmol/L (metabolic acidosis group) or 22 to ⁇ 30 mmol/L (normal serum bicarbonate group) with a minimum of 3 years of health system engagement prior to the first qualifying serum bicarbonate test.
  • Serum bicarbonate and eGFR values from hospital inpatient or emergency care involving diagnosed acute kidney injury were not used in this study, as these could represent acute conditions.
  • the first serum bicarbonate value in the qualifying pair established the baseline serum bicarbonate value and the study index date.
  • Patients with evidence of dialysis (by procedure code, diagnosis code, or an outpatient eGFR ⁇ 10 mL/min/1 ,73m 2 ) or kidney transplantation preindex were excluded (Table 1).
  • the primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate, which was calculated as the difference from baseline serum 84 bicarbonate value to every serum bicarbonate test during the outcome period until the outcome event, death, or censoring at the end of EHR data.
  • the number of days from index to each subsequent serum bicarbonate test was also retained for use in timedependent modeling.
  • Baseline comorbidities personal history of kidney stones, diabetes, hypertension, gallstones, gout, hyperoxaluria, non-alcoholic fatty liver disease, osteoporosis
  • Comorbid metabolic syndrome required three elements: baseline hypertension, index triglycerides >150 mg/dL, and high-density lipoprotein (HDL) cholesterol ⁇ 40 mg/dL for females and ⁇ 35 mg/dL for males.
  • HDL high-density lipoprotein
  • Age was assessed at index based on year of birth; as part of the deidentification process, all birth years before 1930 were normalized to 1930 due to privacy concerns.
  • Racial group was combined from separate race and ethnicity variables as follows: patients identified with Caucasian or other/unknown race and Hispanic ethnicity were assigned to the Hispanic group, with remaining Caucasians classified as nonHispanic Whites; those identified as African American or Asian were classified as Black or Asian, respectively, irrespective of ethnicity. Gender and region (the US Census region of the patient’s residence) were supplied by the data vendor.
  • baseline eGFR was established as the most proximal 90-day average of all eGFR values >10 and ⁇ 60 mL/min/1 .73 m 2 occurring on or before the index date; same-day results were averaged to contribute singly to the mean. Patients were stratified by CKD stage using baseline eGFR.
  • kidney stone(s) defined as the first post-index occurrence of diagnosis code for kidney stones (ICD-9 codes 592, 594, 274.11 (Rule et al. 2009) and ICD-10 codes N20.0-N22.8 (Alexander et al. 2012)). Diagnosis codes with a status of “possible” and those pertaining to personal or family history were excluded.
  • kidney stone hospitalizations defined as an inpatient hospitalization beginning on or after the index date with a concurrent diagnosis code for kidney stones.
  • the hazard at time t was evaluated on the value of the covariates at that time.
  • a Fine and Gray model was used to evaluate risk of kidney stone development, with death as a competing risk. All models were adjusted for age group (4 categories, with age 65-74 years as the comparison), sex, race, geocoded education level, low-income status, obesity, smoking history, baseline eGFR, baseline comorbidities (personal history of kidney stones, diabetes, hypertension, gallstones, gout, hyperoxaluria, non-alcoholic fatty liver disease, osteoporosis, dyslipidemia, personal history of bariatric surgery) and baseline urine specific gravity. Missing data on smoking, income status and dyslipidemia were handled by including “missing data” as a value in these categorical fields. Complete data was required on all other covariates.
  • the percentage of patients experiencing one or more kidney stone-related hospitalizations was evaluated on an unadjusted basis during the outcome period and compared between the metabolic acidosis and normal serum bicarbonate groups.
  • the unadjusted frequency of kidney stone-related hospitalizations during the outcome period was evaluated as the rate of admissions per 1000 patient-years, allowing for consideration of multiple admissions per patient, and compared between the metabolic acidosis and normal serum bicarbonate groups by Poisson regression.
  • CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
  • CPT Current Procedural jrminology®
  • eGFR estimated glomerular filtration rate
  • EMR electronic medical record
  • HCPCS Healthcare Common ocedural Coding System
  • ICD-CM International Statistical Classification of Diseases and Related Health Problems, Clinical odification
  • CKD chronic kidney disease
  • eGFR estimated glomerular filtration rate
  • SD standard deviation
  • Fhe primary analysis cohort is a subset of the full study cohort for which complete urine specific gravity data and at least one >st-index serum bicarbonate measurement was available. ible 3. Missing data on laboratory values and other characteristics.
  • Sensitivity analysis time-dependent Cox PH model omitting urine specific gravity as a covariate
  • citrate In the urine, citrate binds calcium, leading to a reduction in the ability of calcium to complex with oxalate or phosphate and form a solid phase (Parmar, 2004; Dey et al. 2002). Metabolic acidosis increases citrate reabsorption in the proximal tubule and results in decreased urine citrate excretion, leading to an increased potential for calcium containing stone formation. Indeed, oral potassium citrate, an alkali that increases urine citrate excretion, reduces recurrent stone formation (Fink et al. 2013; Skolarikos et al. 2015).

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Abstract

L'invention concerne des compositions pharmaceutiques et des méthodes de traitement d'un individu atteint de la ladite maladie (c'est-à-dire un animal, notamment un être humain). Les compositions pharmaceutiques contiennent une composition non absorbable et peuvent être utilisées, par exemple, pour traiter une lithiase.
PCT/US2022/046405 2021-10-13 2022-10-12 Compositions pharmaceutiques destinées au traitement d'une lithiase WO2023064357A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509013B1 (en) * 1993-08-11 2003-01-21 Geltex Pharmaceuticals, Inc. Method of making phosphate-binding polymers for oral administration
US7459502B2 (en) * 2003-11-03 2008-12-02 Ilypsa, Inc. Pharmaceutical compositions comprising crosslinked polyamine polymers
US8192758B2 (en) * 2004-03-30 2012-06-05 Relypsa, Inc. Ion binding compositions
US20140221964A1 (en) * 2011-03-27 2014-08-07 Yong-Fu Xiao Systems and methods for local drug delivery to kidneys
US20200289551A1 (en) * 2017-11-03 2020-09-17 Tricida, Inc. Compositions for and method of treating acid-base disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509013B1 (en) * 1993-08-11 2003-01-21 Geltex Pharmaceuticals, Inc. Method of making phosphate-binding polymers for oral administration
US7459502B2 (en) * 2003-11-03 2008-12-02 Ilypsa, Inc. Pharmaceutical compositions comprising crosslinked polyamine polymers
US8192758B2 (en) * 2004-03-30 2012-06-05 Relypsa, Inc. Ion binding compositions
US20140221964A1 (en) * 2011-03-27 2014-08-07 Yong-Fu Xiao Systems and methods for local drug delivery to kidneys
US20200289551A1 (en) * 2017-11-03 2020-09-17 Tricida, Inc. Compositions for and method of treating acid-base disorders

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