MXPA06011210A - Methods and compositions for treatment of ion imbalances - Google Patents

Abstract

The present invention provides methods and compositions for the treatment of ion imbalances. In particular, the invention provides compositions comprising sodium-binding polymers and pharmaceutical compositions thereof Methods of use of the polymeric and pharmaceutical compositions for therapeutic and/or prophylactic benefits are disclosed herein. Examples of these methods include the treatment of hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, chronic renal insufficiency, fluid overload, or sodium overload.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF IONAL IMBALANCES BACKGROUND OF THE INVENTION Currently, approximately 58 million American adults have hypertension and the direct and indirect costs of hypertension are estimated to be more than a quarter of a billion dollars per year. It is considered that hypertension is the main causative factor of stroke and is associated with a high rate of morbidity and mortality when diagnosed in its final stages. Hypertension is a condition characterized by high blood pressure, that is, systolic pressure consistently greater than about 140 or diastolic blood pressure consistently greater than about 90. Many factors affect high blood pressure, including the volume of fluid present in the blood. body, the salt content of the body, the state of the kidneys, the nervous system or blood vessels, and the levels of various hormones present in the body. 35% of Caucasian patients with hypertension and 65% of African-American patients with hypertension are characterized by having salt / water retention. Hypertension and diabetes are the most common causes of end-stage renal disease (NFT). The non-pharmacological approach to treat hypertension consists of salt restriction, weight control and stress control. The control of sodium intake prevents one third of cases of hypertension and is a useful complementary therapy in another third of cases. The National Heart, Lung, and Blood Institute (NHLBI) recommends, as part of a total healthy diet, that Americans consume no more than 2.4 g (100 mmol) of sodium per day . This is equal to approximately 6 g of sodium chloride. However, it is estimated that the average diet of Americans consists of 8 to 12 g of salt per day. In fact, the recommended intake of salt is even lower for patients with advanced stage nephropathy and people who are at risk of developing hypertension. Common treatments for hypertension include calcium channel blockers, diuretics, beta blockers, alpha blockers, medications for anxiety, ACE inhibitors, and vasodilators. Recent studies recommend that diuretics be used as the preferred single initial treatment or as part of a combination treatment for patients suffering from hypertension. Diuretics are drugs that increase the rate of urine flow by interfering with the reabsorption of sodium and water in the nephroids. In general, diuretics increase the body's rate of sodium excretion. Sodium is the main determinant of the volume of water outside the cells (referred to as extracellular water). A diuretic that causes the excretion of sodium in the urine reduces the volume of extracellular water. The increase in sodium excretion restores salt homeostasis and the lower tonicity that ultimately results in lower blood pressure. While the body regulates the concentration of intracellular and extracellular sodium within very narrow limits, the excretion of salt is usually accompanied by the loss of a proportional amount of water. Diuretics belong to four categories, depending on their mode and locus of action: Carbonic anhydrase inhibitors, such as acetazolamide, which inhibit the absorption of NaHCO3 and NaCl in the proximal tubule; Loop diuretics, such as furosemide, which act on the loop of Henle inhibiting NaMK + / 2Cl transporters "; Thiazide diuretics, which inhibit the Na + / Cl ~ cotransporters in the distal tubule; Potassium-sparing diuretics, which act in the collecting tubule and reduce the absorption of sodium while not causing loss of K + (ie, as opposed to the other three categories, which promote the loss of potassium.) Diuretics are not always effective therapies, since they have unwanted side effects. The imbalance in the anions induced by the modification of sodium transport tends to create complications, such as acidosis or alkalosis. One of the limitations of diuretic therapy is "resistance to diuretics." A definition of resistance to diuretics is the inability to excrete at least 90 mmol of sodium within 72 hours after taking a dose of 160 mg of furosemide administered orally twice a day. This effect is caused by a mechanism or a combination of mechanisms: (i) a change in the pharmacokinetic profile of loop diuretics, (ii) compensation of sodium absorption in the distal nephroids, and (iii) decreased nephrogenic response . Loop diuretics, such as furosemide, have a maximum plasma concentration where fractional sodium excretion is maximal. This effect of maximum concentration has important implications for patients who barely respond to submaximal concentrations. These patients require continuous infusion of the drug to achieve the desired level of sodium excretion. Despite several attempts to improve the profile of the drug or its bioavailability, the results of these therapies are still lower than what would be desirable. It is believed that resistance to diuretics occurs in one in three patients with congestive heart failure (ICC). Because patients who are prescribed a diuretic should follow a diet low in sodium, another cause of failure of diuretic therapy is the inability of patients to comply with such a low-salt diet. Edema refers to the accumulation of abnormally high volumes of fluid in the intercellular space of the body as a result of excessive sodium retention. Edema may be associated with renal failure, nephritic syndrome, nephrotic syndrome, heart failure or liver failure. When the mechanisms that regulate the balance of sodium in the body are altered, the accumulation of sodium produces a compensatory accumulation of fluid (to rectify the osmotic imbalance) and observable edema. In patients whose kidneys function properly, edema can be treated by limiting sodium intake and by the use of diuretics, which causes the body to excrete more water in the urine (Brater, DC (1992), "Clinical pharmacology of loop diuretics in health and disease ", Eur Heart J 13 Suppl G: 10-4, and Brater, DC (1993)," Resistance to diuretics: mechanisms and clinical implications ", Adv Nephrol Necker Hosp 22: 349-69). Diuretics are ineffective in patients with impaired renal function and also in certain patient populations that do not respond to diuretics (Brater, DC (1981), "Resistance to diuretics: emphasis on a pharmacological perspective", Drugs 22 (6 ): 477-94, and Brater, DC (1985), "Resistance to loop diuretics, Why it happens and what to do about it", Drugs 30 (5): 427-43). Several studies have shown that it is possible to trap and eliminate intestinal sodium. However, the amount of resin required for this purpose (generally 60 to 100 g / day) is considered unacceptably high for modern therapy. Large doses reflect the low in vitro and lower binding capacity in vivo of these resins. Even in the presence of high sodium diets, sulfonic resins do not remove more than 1 meq NaVg / carboxylic resins no more than 2 meq NaVg and phosphonic resins no more than 0.8 meq NaVg (Fourman, P. (1953) , "Capacity of a cationic exchange resin (zeo-karb 225) in vivo", Br Med J 1 (4809): 544-6; Heming, AE and TL Flanagan (1953), "Considerations in the selection of cation-exchange resins for therapeutic use ", Ann NY Acad Sci 57 (3): 239-51; and McChesney, EW, FC Nachod, et al., (1953)," Some aspects of cation exchange resins as therapeutic agents for sodium removal ", Ann NY Acad Sci 57 (3): 252-9). Typically, the resins retained only about 25% or less of their sodium binding capacity in vi tro when used clinically in patients. These resins were not well tolerated by patients due to their sandy or creamy texture and due to their tendency to cause constipation (Heming, AE and TL Flanagan (1953), "Considerations in the selection of cation-exchange resins for therapeutic use", Ann NY Acad Sci 57 (3): 239-51). Therefore, it would be beneficial to develop polymeric compositions that efficiently remove salt and / or water from the gastrointestinal tract. In addition to patients with hypertension, patients suffering from end-stage renal disease, renal failure, chronic diarrhea, incontinence, congestive heart failure, liver cirrhosis, idiopathic edema, and other conditions may benefit from intestinal Na + fixation and / or intestinal water. . In general, current treatments to reduce salt and / or water levels in the body are suboptimal. Accordingly, there is a need to develop selective therapies of high capacity to eliminate salt and / or water, with fewer side effects for patients.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a schematic representation of the formation of a polyelectrolyte complex. FIG. 2 shows the permeability of the membrane to sodium at different pH.

BRIEF SUMMARY OF THE INVENTION The present invention provides methods for removing sodium from the gastrointestinal tract of an animal. In some embodiments, the methods generally involve the administration of an effective amount of a sodium-binding polymer. Preferably, the sodium-binding polymers have a sodium binding capacity in vivo in a human being of 4 mmol or more per g of polymer. In other embodiments, the methods involve the administration of core-shell compositions to remove sodium from the gastrointestinal tract. The methods and compositions described herein are useful in the treatment of disorders in which the removal of sodium and / or water from the body of a human being is desirable. Diseases that can be treated with the methods and compositions described herein include, but are not limited to, hypertension, chronic heart failure, end-stage renal disease, liver cirrhosis, chronic renal failure, fluid overload, or overload of sodium.

DETAILED DESCRIPTION OF THE INVENTION Sodium-binding polymeric compositions The present invention provides methods, pharmaceutical compositions and kits for the treatment of animal patients. The term "animal patient" and the term "animal", as used herein, include humans, as well as other mammals. In particular, the present invention provides polymer compositions for removing sodium ions. Preferably, these compositions are used to remove sodium ions from the gastrointestinal tract of animal patients.

One aspect of the invention is a method for removing sodium ions with a sodium-binding polymer composition. In one embodiment, the sodium-binding polymer composition has a high capacity and / or selectivity to fix sodium and does not significantly release fixed sodium in the gastrointestinal tract. Preferably, the sodium-binding polymer composition does not release the fixed sodium in the colon. Even more preferably, the sodium-binding polymer composition does not introduce harmful ions. It is preferred that the polymer composition exhibits a selective binding of the sodium ions. In one embodiment, due to the selective binding of sodium by the sodium fixing polymeric composition, the composition does not remove the potassium from the body. It is preferred that the polymer compositions of the present invention have a high capacity and / or selectivity of sodium fixation. The term "high capacity", as used herein, encompasses the in vivo fixation of 4 mmol or more of sodium per g of polymer. Typically, this binding capacity in vivo is determined in a human being. The techniques for determining the binding capacity of sodium in vivo in a human being are well known in the field. For example, after administration of a sodium-binding polymer to a patient, the amount of sodium present in the stool can be used to calculate the sodium binding capacity in vivo. Typically, the ability to bind sodium in vivo is determined in a human being who is not deficient in a hormone that controls the excretion of salt, e.g. , aldosterone. In some embodiments, the binding capacity of sodium in vivo may be equal to or greater than 4 mmol per g of polymer in a human. Preferably, the binding capacity of sodium in vivo in a human being is about 5 mmol or more per g, more preferably is about 6 mmol or more per g, even more preferably is about 7 mmol or more per g, and most preferably is approximately 8 mmol or more per g. In a preferred embodiment, the binding capacity of sodium in vivo in a human being is from about 8 mmol to about 15 mmol per g in a human. The capacity of the sodium fixing polymers can also be determined in vitro. It is preferred that the in vitro sodium binding capacity be determined under conditions that simulate the physiological conditions of the gastrointestinal tract. In some embodiments, the in vitro binding capacity of sodium is determined in solutions with a pH of about 7.5 or less. In various embodiments, the binding capacity of sodium in vi tro at a pH of about 7.5 or less is equal to or greater than 6 mmol per g of polymer. A preferred range of the sodium binding capacity in vi tro at a pH of about 7.5 or less is from about 6 mmol to about 15 mmol per g of polymer. Preferably, the ability to bind sodium in vi tro at a pH of about 7.5 or less is equal to about 6 mmol or more per g, more preferably is about 8 mmol or more per g, even more preferably is about 10 mmol or more. per g and most preferably it is about 15 mmol or more per g. The higher capacity of the polymer composition allows the administration of a lower dose of the composition.

Typically, the dose of the polymer composition used to obtain the desired therapeutic and / or prophylactic benefits is from about 0.5 g / day to about 25 g / day. Most preferred is about 15 g / day or less. A preferred dose range is from 5 g / day to approximately 20 g / day, more preferred is from approximately 5 g / day to approximately 15 g / day, even more preferred is from approximately 10 g / day to approximately 20 g / day and most preferred is from about 10 g / day to about 15 g / day. The term "noxious ions" is used herein to refer to ions that are not desired to be released to the body by the compositions described herein during their period of use. Typically, the ions harmful to a composition depend on the condition being treated, the chemical properties and / or the binding properties of the composition. For example, when hypertension is being treated and the composition is used to remove sodium ions, the harmful ions would be chloride or OH ", since these patients frequently have alkalosis.When kidney failure is being treated, the examples of harmful ions are K + and Ca2 + It is also preferred that the compositions described herein retain a significant amount of the fixed sodium Preferably, the sodium is fixed by the polymer in the upper gastrointestinal tract and is not released into the lower gastrointestinal tract. "significant amount", as used in this document, does not mean that the entire amount of sodium fixed is retained, it is preferred that at least a little of the sodium fixed be retained, so that a therapeutic benefit is obtained and / or prophylactic The preferred amounts of fixed sodium that are retained range from about 5% to about 100%. that the polymer compositions retain approximately 25% of the fixed sodium, it is more preferred that they retain approximately 50%, it is even more preferred that they retain approximately 75% and that it is most preferred that they retain 100% of the fixed sodium. The retention period is preferably during the time that the composition is being used therapeutically and / or prophylactically. In the embodiment in which the composition is used to fix and remove sodium from the gastrointestinal tract, the retention period is the residence time of the composition in the gastrointestinal tract. In one embodiment, the sodium-binding polymer composition exchanges protons for sodium ions in the upper gastrointestinal tract and keeps the sodium fixed within the polymer composition in the colon, where the sodium concentration is typically much lower compared to other cations . The latter are typically K +, Mg ++, Ca ++, NH4 +, H + and protonated amines derived from the enzymatic deamination of amino acids, which are referred to herein as "competing cations". In another embodiment, the sodium-binding polymer composition is characterized by a high rate of sodium ion fixation (against competing cations), even in an environment in which the sodium: competing cations ratio is as low as 1: 4, as for example in the colon. In yet another embodiment, the sodium-binding polymer composition is characterized by a high, but non-specific, sodium fixation in the upper tract, associated with a decrease in the ionic permeability of the resin triggered by a change in the physiological conditions of the tract. gastrointestinal This change in permeability can be effected by a change in the pH of the stomach to the duodenum or a change in the pH of the ileum to the colon. In another embodiment, the change in permeability can be effected by the presence of a secretion (such as bile acids) or metabolites (such as fatty acids), or localized enzymatic activity. In an embodiment, the sodium-binding polymer composition comprises an acid type resin, preferably loaded with H + or N? 4M and possibly KM Typically, H + and NH4 + are displaced in the upper tract mainly by Na + and the permeability of the resin to the ions it is reduced as the resin circulates from the upper gastrointestinal tract to the lower gastrointestinal tract. Typically, this change in permeability is modulated by the physiological changes in the environment of the various gastrointestinal segments. In another embodiment, the sodium fixing polymer composition comprises sulfonate or phosphonic polymers.

Sodium-binding core-shell compositions In one aspect of the invention, a core-shell composition is used for the removal of sodium. Typically, in core-shell compositions, the core comprises a polymer with a high sodium binding capacity. The various polymeric sodium-binding compositions described herein can be used as the core component of the core-shell compositions. In some embodiments, the envelope modulates the entry of competing solutes through the envelope to the core component. In one embodiment, the permeability of the bound sodium membrane is reduced as the core-shell composition circulates through the gastrointestinal tract. Typically, this change in permeability is produced by an increase in hydrophobicity and / or a deflation of the envelope. It is preferred that, essentially, the envelope of the core-shell composition does not disintegrate during the period of residence and transit through the gastrointestinal tract. The term "competing solute," as used herein, means solutes that compete with sodium for binding to a core component, but which are not intended to come in contact with and / or bind with the core component. . Typically, the competing solute for a core-shell composition depends on the core fixing characteristics and / or the permeability characteristics of the shell component. A competing solute can be prevented from coming into contact and / or binding with a core-shell particle due to the preferential fixation characteristics of the core component and / or the decrease in the permeability of the shell component for the competing solute of the external environment. Typically, the competing solute has a lower permeability from the external environment through the shell as compared to that of the sodium ions. Examples of competing solutes include, but are not limited to, K +, Mg ++, Ca ++, NH4 +, H + and protonated amines.

In a preferred embodiment, the core-shell composition fixes sodium through the gastrointestinal tract, but prevents the release of sodium in the colon. These properties of the core-shell are modulated by the fact that the shell is permeable to sodium in the upper parts of the gastrointestinal tract and is less permeable to sodium in the lower gastrointestinal tract, such as the proximal colon. This modulation of the permeability of the envelope through the gastrointestinal tract is referred to herein as the "permeability trap". In some embodiments, the shell is permeable to both monovalent and divalent cations. In some of the embodiments in which the shell is permeable to both monovalent and divalent cations, the core fixes only monovalent cations, preferably sodium, due to the fixing characteristics of the core. In other embodiments, the wrapper exhibits preferred permeability to sodium ions. It is especially preferred that the core-shell compositions and the sodium-binding polymeric compositions described herein bind sodium in the parts of the gastrointestinal tract having a relatively high concentration of sodium, such as from about 70 mM to about 140 mM. It is then preferred that this fixed sodium remains fixed to the compositions and that it is not released in the parts of the gastrointestinal tract having a relatively lower sodium concentration, such as, for example, from about 10 mM to about 40 mM.

In one embodiment, the wrapping material protects the core component against the external Gl environment. In some embodiments, the wrapping material protects the acid groups from the core polymer and prevents their exposure to the Gl environment. In one embodiment, the core component is protected with a shell component comprising an enteric coating. Suitable examples of enteric coatings are described in the art. For example, see Remington: The Science and Practice of Pharmacy, by A.R. Gennaro (Editor), 20- Edition, 2000. In another embodiment, the wrapping material is designed to respond to physiological changes in the gastrointestinal tract, so as to alter the permeability of the wrapping. The permeability of the envelope is reduced so that the hydrophilic ions can no longer pass through the envelope membrane after these ions are fixed to the core. Preferably, this decrease in permeability occurs during the period of use of the polymer composition, ie, during the period in which the polymer composition resides in the gastrointestinal tract. The loss of permeability to hydrophilic ions can be achieved by reducing or even eliminating the free permeation volume of the membrane. Since the latter is controlled for the most part by the hydration rate of the envelope, it is possible to cancel the permeation rate almost completely by inducing a collapse of the envelope. Many techniques are known in the field to induce said phase change. The preferred approach is to make the membrane material increasingly hydrophobic so that the hydration rate decreases to almost zero. This can be achieved in several ways, depending on the type of trigger mechanism. For example, the phase change can be triggered by a pH change. The pH profile of the gastrointestinal tract may change as a function of time, but shows some invariants, as indicated below in TABLE 1 (Fallinborg et al., Aliment, Pharm. Therap. (1989), 3, 605- 613): TABLE 1 Shell polymers that exhibit a chain collapse in any of these pH regions can be used to cause changes in permeability. An embodiment of the core-shell particles selectively binds sodium ions in the stomach and holds them in the core of the particles as they go down the small and large intestine and show high permeability to sodium ions at low pH and a very low permeability at neutral pH. This can be achieved by having a shell polymer with hydrophobic groups and groups that are ionized subject to changes in pH. For example, polymers formed from hydrophobic monomers (e.g., (meth) acrylates of long-chain alcohols, N-alkyl (meth) acrylamide, aromatic monomers) and basic monomers that ionize at low pH and remain neutral beyond their pKa (eg, vinylpyridine, dialkylaminoethyl (meth) acrylamide). The relationship between the pH and the swelling ratio of the shell, and hence the permeability, is controlled by the equilibrium of hydrophobic monomers and ionizable monomers. Examples of such systems have been reported in the literature (Batich et al., Macromolecules, 26, 4675-4680). In one embodiment, the envelope of a core-shell composition is characterized by a high permeability to sodium at low pH, such as a pH of about 1 to about 5. A core-shell with these properties can fix sodium in the stomach and , as the composition passes through the lower gastrointestinal tract, the permeability is interrupted, typically at an approximately neutral pH. In one embodiment, the envelope of the core-shell composition is characterized by a high permeability to sodium at approximately neutral and higher pH. A core-shell with this property can absorb and fix sodium in the upper gastrointestinal tract of secretions that are mostly rich in sodium (eg, about 140 mM in sodium and approximately 20 mM in potassium) and when the composition enters into the caecum, where the pH range is from about 5 to about 6, the envelope collapses and reduces its permeability to competing cations. The wrapping material changes from a hydrated state to a collapsed-impermeable state as the pH becomes slightly acidic. In this particular case, the shell polymers typically contain a balanced amount of hydrophobic monomers and acidic monomers. In the literature, systems that can be used in the envelope of this embodiment have been described. For example, see Kraft et al., Langmuir, 2003, 19, 910-915; Ito et al., Macromolecules, (1992), 25.7313-7316. In another embodiment, the wrapping of a core-shell composition exhibits a change in permeability caused by passive absorption as it passes through the upper Gl tract. Many components present in the Gl tract, including dietary components, metabolites, secretion, etc., are susceptible to adsorption on and within the envelope in an almost irreversible manner and strongly modify the pattern of permeability of the envelope. The vast majority of these soluble materials are negatively charged and show various levels of hydrophobicity. Some of these species have a typical amphiphilic nature, such as fatty acids, phospholipids and bile salts, and behave as surfactants. Surfactants can be adsorbed, not specifically on surfaces, through hydrophobic interactions, ionic interaction and combinations thereof. In this embodiment, this phenomenon is used to change the permeability of the polymer composition in the course of fixing sodium ions. In one embodiment fatty acids can be used to modify the permeability of the envelope and in another embodiment bile acids can be used. Both fatty acids and bile acids form aggregates (micelles or vesicles) and can also form insoluble complexes when mixed with positively charged polymers (see, for ex. , Kaneko et al., Macromolecular Rapid Communications (2003), 24 (13), 789-792). Both fatty acids and bile acids have similarities with synthetic anionic surfactants and numerous studies report the formation of insoluble complexes between anionic surfactants and cationically charged polymers (eg, Chen, L. et al., Macromolecules (1998), 31). (3), 787-794). In this embodiment, the wrapping material is selected from copolymers containing both hydrophobic and cationic groups, so that the shell forms a complex tightly bound with the anionically charged hydrophobes typically found in the Gl tract, such as bile acids, acids fatty acids, bilirubin and related compounds. Suitable compositions also include polymeric materials described as bile acid sequestrants, such as those reported in U.S. Pat. 5,607,669; 6,294,163; and 5,374,422; Figuly et al, Macromolecules, 1997, 30, 6174-6184. The formation of the complex induces a collapse of the envelope membrane which in turn can reduce or even cancel the permeation rate through the membrane. A core-shell with these properties can absorb and fix sodium in the upper gastrointestinal tract, such as in the stomach and duodenum, and as the bile acid and fatty acid molecules are attached to the envelope lower in the stomach. gastrointestinal tract, the permeability of the envelope to the ions, including sodium, is reduced as the porosity of the envelope is hindered by the bile acid molecules and / or fatty acids. In addition, an interaction between bile acids and fatty acids with the envelope prevents their interaction with the nucleus and therefore may preserve the sodium binding capacity of the core component. In yet another embodiment, the permeability of the envelope of a core-shell composition is modulated by the enzymatic activity in the gastrointestinal tract. There are several secreted enzymes that are produced by the common colonic microflora. For example, Bacteroides, Prevotella, Porphyromonas and Fusobacterium produce a variety of secreted enzymes, including collagenase, neuraminidase, deoxyribonuclease [DNase], heparinase and proteinases. In this embodiment, the envelope comprises a hydrophobic backbone with pendant hydrophilic moieties that are detached through an enzymatic reaction in the intestine. As the enzymatic reaction proceeds, the polymeric membrane becomes increasingly hydrophobic and changes from a material with a high rate of permeability in a highly swollen state to a membrane with low hydration, completely collapsed and with minimal permeability. Hydrophilic entities can be chosen from natural substrates of enzymes commonly secreted in the Gl tract. Such entities include amino acids, peptides, carbohydrates, esters, phosphate esters, oxyphosphate monoesters, O- and S-phosphorothioates, phosphoramidates, thiophosphate, azo groups and other similar entities. Examples of enteric enzymes susceptible to chemically alter the shell polymer include, but are not limited to, lipases, phospholipases, carboxylesterase, glycosidases, azorreductases, phosphatases, amidases and proteases. The envelope may be permeable to sodium ions until it enters the proximal colon and then enzymes present in the proximal colon may chemically react with the envelope to reduce its permeability to sodium ions. In some embodiments, the thickness of the wrapper can be between about 0.002 microns and about 50 microns, and preferably between about 0.005 microns and about 20 microns. Preferably, the thickness of the envelope is more than about 1 micron, more preferably is more than about 10 microns, even more preferably is more than about 20 microns and most preferably is more than about 40 microns. Preferably, the thickness of the envelope is less than about 50 microns, more preferably it is less than about 40 microns, even more preferably it is less than about 20 microns and most preferably it is less than about 10 microns. The size of the core-shell particles generally ranges from about 200 nm to about 2 mm and is preferably about 500 μm. Preferably, the size of the core-shell particles is more than about 1 μm, more preferably is more than about 100 μm, even more preferably is more than about 200 μm and most preferably is more than about 400 μm. Preferably, the size of the core-shell particles is less than about 500 μm, more preferably it is less than about 400 μm, even more preferably it is less than about 200 μm and most preferably it is less than about 100 μm. Sodium-fixing Polymers In one embodiment, the sodium-binding polymer used in the polymer compositions and the core-shell compositions is a functional polymer of the sulfonic (-S03"), sulfuric (-OSO3" "), carboxylic (-C02) type polymer. ~), phosphonic (-P03 ~), phosphoric (- (OPO3") or sulfamate (-NHSO3"). Free radical polymers derived from monomers such as vinylsulfonate, vinylphosphonate or vinyl sulfamate can also be used. fix sodium over wide pH range Examples of other monomers suitable for sodium fixing polymers are included in Table 2.

TABLE 2; Examples of cation exchange units structures and theoretical fixation capabilities Mass Fraction Molar fraction of Hde HCapacityCapacity by titulabletitulable capacity expected expected Other cation exchange units that are suitable include: where n is equal to or greater than one and Z represents S03H or P03H.

Preferably, n is about 50 or more, more preferably n is about 100 or more, even more preferably n is about 200 or more, and most preferably n is about 500 or more. Suitable phosphonate monomers include vinylphosphonate, vinyl 1,1-bis-phosphonate and ethylenic derivatives of phosphonocarboxylate esters, oligo (methylenephosphonates) and hydroxyethane-1,1-diphosphonic acid. The methods of synthesis of these monomers are well known in the art. Sulfamic polymers (ie, when Z = S03H) or phosphoramidic polymers (ie, when Z = P03H) can be obtained from polymers of amines or precursors of monomers treated with a sulfonating agent, such as sulfur trioxide / amine adducts or a phosphonating agent, such as P20s, respectively. Typically, the acid protons of the phosphonic groups are interchangeable with cations, such as sodium, at a pH of about 6 to about 7. Another example of a monomer suitable for use in the present invention is a-fluoroacrylate. This monomer is typically prepared from chloroacetate ester. See KF Pittman, C. U., M. Ueda, et al., (1980). Macromolecules 13 (5): 1031-1036. Other methods comprise step growth polymerization from functional phosphonate, carboxylic and phosphate, sulfinate, sulfate and sulfonate functional compounds. High density polyphosphonates, such as those marketed by Rhodia under the trademark Briquest, are particularly useful. The polymers of the invention also include ion exchange resins synthesized from natural polymers, such as saccharide polymers, and semi-synthetic polymers, optionally functionalized to create ion exchange sites in the backbone or in the pendant residues. Examples of polysaccharides of interest include materials of vegetable or animal origin, such as cellulosic materials, hemicellulose, alkylcellulose, hydroxyalkylcellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectin, chondroitin, hiarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin. and chitosan. Most preferred are polymers that do not degrade under the physiological conditions of the gastrointestinal tract and remain unabsorbed, such as carboxymethylcellulose, chitosan and sulfoethylcellulose. Cation and Anion Fixing Polymers An embodiment of the invention utilizes either an acid resin (eg, sulfonate in protonic form) or a strong base resin (eg, quaternary ammonium in OH form) or a weak basic resin (eg. example, a free amine.) This composition can release water upon exchange of H + by Na + and OH "by Cl." In yet another embodiment, the polymer contains an internal salt of an acid and a basic function, free of counterions. In this embodiment, the combination with an anion-fixing resin has the advantage of increasing the excretion of chloride ions from the body (the most dominant anion in the environment of the upper Gl tract) and therefore minimizing acidosis in patients who have In one embodiment, the polymeric composition that can bind sodium has the ability to swell from about 2 to about 100 times its weight in a liquid composition. In one embodiment, the polymer is an acid-stable liquid-absorbent polymer that can absorb from about 10 to about 50 times its weight in saline and has the ability to retain this liquid absorbed under pressure., for example, under pressure that occurs when volume reduction occurs in the human colon. Based on the structure of the polymer, the absorption of liquids can be pH dependent and the absorption of saline can be prevented in the stomach and occur in the gastrointestinal tract. The liquid absorption site can be modified based on the structure of the polymer, including by crosslinking, counterions, molecular weight, charge density, crosslinking density or coatings. In one embodiment, the invention utilizes a cation exchange resin in acid form and an anion-binding resin in basic form, ie, the anion exchange site positively charged in the polymer is compensated by OH. "Alternatively, the polymer can be a free base that is protonated upon contact with aqueous gastrointestinal liquid Resins can independently be water soluble materials or cross-linked materials; preferably, both resins are crosslinked. The molar ratio of the anion exchange (OH ") to the cation exchange (H +) is preferably from about 0.5 to about 1.5 and most preferably from about 0.9 to about 1.1.The ion exchange resins can be obtained by free radical polymerization , copolymerization of functional monomers, post-functionalization of polymers or combinations thereof Examples of cation exchange groups are those shown in Table 2. Examples of anion exchange groups are: amine (-NR3), quaternary ammonium ( -NR4 +), amidine (-C (= NH) -NH2), guanidine (-NH-C (= NH) -NH2) and phosphonium (-PR3 +) .The methods of preparation of the polymers with ion exchange resins are well known to people who master the technique, for example, see Ion Exchange, Charles Dickert, Kirk-Othmer Encyclopedia of Chemical Technology, ® 1995, by John Wiley &Sons, Inc. Resins in Ion exchangers can be prepared by means of a variety of processes, including block, solution, emulsion, suspension, dispersion or precipitation, or with the use of water or organic solvents. When necessary, process aids are used, including free radical initiators, redox initiation systems, crosslinking agents, branching agents, chain transfer agents, suspending agents, wetting agents, stabilizers, porogén, diluents, photostabilizers, thermostabilizers and plasticizers. The polymer can be in the form of, for example, powder, globule, sheet, fiber, capsule or membrane. It is preferred that the ion exchange capacities of the polymers described herein be maximum to retain the highest salt load (eg, expressed as NaCl). The higher the capacity, the lower the dose of polymer required to excrete a given amount of salt. The capacity can be expressed as interchangeable ion meq per gram of polymer. The weight of the sodium chloride absorbed by one gram of polymer as a function of the polymer capacity can be calculated as follows: PNaC1 = 58.44.10"3 / (CaAMCcat" 1), where Can is the capacity of the exchange resin of anions and Ccat is the capacity of the cation exchange resin. In preferred embodiments of the present invention, Ppací ranges from about 0.05 to about 1, preferably from about 0.2 to about 0.7, and most preferably from about 0.3 to about 0.5. Can and Ccat are preferably between about 2 and about 30 meq / g, preferably about 5 to about 25 meq / g, and most preferably between about 10 and about 20 meq / g.

Some examples of suitable anion exchange polymers are: In these structures, N represents a nitrogen atom attached to substituents to respect the valence of nitrogen: examples of substituents are indicated below (but are not limited to these): -NR2, -N + R3, -NR-CH = NR, -NR-C (= NR) NR2, where R is H, alkyl, aryl or acyl, optionally substituted. Anion exchange resins can also be synthesized from natural polymers, such as saccharide polymers, and semi-synthetic polymers, optionally functionalized to introduce an amino functionality into the skeleton or the pendant residues. They can be prepared by nucleophilic substitution reactions under alkaline conditions. A Michael addition can be used to prepare cyanoethylated cellulose or carbamoylcellulose by treating cellulose with acrylonitrile or acrylamide, respectively. The preparation of primary aminoalkyl cellulosic materials generally involves reacting activated cellulose with aminoalkyl halides, aminoalkylsulfuric acid or ethylenimine. Another method of preparing aminoalkyl cellulosic materials involves the direct reduction of the nitrile group of the cyanoethylated cellulose to aminopropyl cellulose. Hoffmann rearrangement of carbamoylethylcellulose with bromine / NaOH for 30 to 120 minutes also gives aminopropylcellulose. The reaction of activated cellulose with epichlorohydrin, followed by subsequent reaction with several diamines, gives 0- [2-hydroxy-3- (α-aminoalkylamino) propylcellulose. A water-soluble 2-aminoethyl-carbamoylcellulose with a low degree of substitution (GS <0.02) can be prepared by treating sodium carboxymethylcellulose with excess ethylenediamine in the presence of water-soluble carbodiimides. In one embodiment, the basic and acidic resins are enclosed in a compartment isolated from the gastrointestinal fluid by an ion-permeable membrane. The use of a membrane to surround resins that are very close reduces the pH variation after salt absorption. For example, the two types of resins can be enclosed in a dialysis bag, a paper bag, a microporous matrix, a polymer gel, hollow fibers, vesicles, capsules, a tablet or a film. In one embodiment, the salt scavenging polymer comprises an internal salt of a polyelectrolyte complex prepared from polymers of opposite charges, where the polymer is capable of removing ions from the gastrointestinal tract and not introducing harmful ions. In this document, reference is made to this material as a polyelectrolyte complex (CPE). The formation of a complex is schematically represented in Fig. 1. A polycation and a polyanion are mixed in a stoichiometric ratio until an insoluble complex precipitates. The CPE is formed as a result of the cooperative electrostatic interaction between the polymers of opposite charges and from a gain of entropy produced by the release of counterions of small molecules. Additional washing or additional dialysis produces a salt-free material: almost all polymer charges are compensated internally. When this material comes in contact with an aqueous solution having a finite salt concentration, and if the salt concentration is sufficiently high, then the coulombic interaction between the polycation and the polyanion is screened by the electric field produced by the added electrolyte. and the complex becomes soluble. In this situation, each charge present in both polymers is compensated by a counterion from the surrounding solution. The net result is that the polymer absorbs salt from the aqueous solution through an ion exchange process. When the CPE is completely solubilized, the amount of salt retained by the polymer is equal to the molar content of internal salt initially present in the polymer complex. In an embodiment, a complex is first formed by adding the two polymers in the required molar ratio to form a complex precipitate, which is subsequently washed to separate it from the liberated salt. When the salt-free polymeric complex is taken orally, upon contact with the gastrointestinal content, the physiological ionic strength is sufficient to cancel the coulombic interaction within the CPE, so that each strand of charged polymer becomes soluble, at once it catches a salt equivalent (mainly NaCl). The polyelectrolytes remain soluble in the gastrointestinal tract and prevent their associated counterions from being reabsorbed until excretion in the faeces. The preparation and physicochemistry of CPEs are well known in the art. For example, see A.S Michael et al., J. Phys. Chem. 65, 1765 (1961).; J. Phys. Chem. 69, 1447 (1965); J. Phys. Chem. 69, 1456 (1965); J. Phys. Chem. 65, 1765 (1961); Bixler et al., Encycl. Polym. Sci. Tech. 10, 765 (1969); Kabanov et al., Chem. Reviews, 4, 207-283 (1982); Tsuchida et al., J. Polym. Sci. Polym. Chem. Ed., 10, 3397 (1972). EPCs are widely used in the art in the microencapsulation of drugs, enzymes, cells, microorganisms, islets of Langerhans, multilayers of polyelectrolytes as sensors, immobilization of proteins by formation of complexes, and polycationic complexes with DNA as vectors in gene therapy. In these prior art applications, CPEs retain a solid gel structure at physiological salt concentrations. However, the CPEs of the present invention undergo salt-induced resolubilization at physiological salt concentrations which in turn allows the polymer to remove salts of the physiological fluid in the gastrointestinal tract. It is preferred that the CPE and the polymers constituting the CPE meet one or more conditions to provide salt removal properties under the conditions prevailing in the gastrointestinal tract: the polymers and their complexes are non-absorbable, non-irritant, non-toxic and non-toxic. inflammatory It is also preferred that the polymers, once they are released from the complex, do not produce a high osmotic pressure, so that significant undesirable intestinal episodes do not occur, such as defecation and osmotic diarrhea. The solubilization of CPE can be triggered by an electrolyte concentration typical of the intestinal tract. The solubilization of CPE can occur at about 50-200 mM, expressed in NaCl, usually about 100 mM. It is further preferred that the polymer, both in gel form and in aqueous solution, does not adversely change the consistency of the feces or cause constipation. The CPEs of the present invention with salt removal properties belong to 3 categories in some embodiments: (i) both polymers are soluble and distinct from one another; (ii) one polymer is a crosslinked gel, while the other polymer is soluble, and the crosslinked material is preferably the cationic component; or (iii) both polymers are co-crosslinked in a gel material. In the CPE in which both polymers are co-criss-crossed in a gel material, a transition from a collapsed state to a swollen state in the presence of salt occurs, where the collapsed gel (the inner salt) begins to absorb the surrounding salt, including NaCl Typically, each CPE has a salt concentration beyond which the complex melts, that is, it solubilizes or swells. This is one of the characteristics of the CPE that controls the salt removal property required in the gastrointestinal environment. The concentration of solubilizing salt (or the concentration of gel swelling salt when a cross-linked gel is used) depends on several factors, such as the charge density of both polymers, the geometric constraints to form an internal salt (charge density coincidence). between the anionic and cationic components), the molecular weights, the total hydrophobicity of the polymer backbones and the molar ratio between the cationic and anionic sites. The polymers of the present invention can be hydrophilic polymers with moderate charge densities, an unevenness in the charge densities between cations and anions, and non-stoichiometric ratios having salt solubilizing properties at salt concentrations in the desired physiological ranges. Preferred ranges of charge densities (expressed as anion or cation capacity in meq / g) are from about 5 meq / g to about 25 meq / g, and most preferably are from 5 meq / g to 10 meq / g. An inequality in the preferred charge density (measured as the ratio of anion capacity to cation capacity: a ratio deviating from 1 results in a density inequality) is from about 0.2 to about 0.8 and from about 1.2 to about 1.8, and most preferably it is from about 0.5 to about 0.8 and from about 1.2 to about 1.5. A preferred stoichiometric ratio of cation / anion is from about 1.00 +/- 0.01 to about 1.00 +/- 0.5 and most preferably is from about 1.00 +/- 0.05 to about 1.00 +/- 0.3.

The polymers of the present invention can be homopolymers or copolymers, and in them the mole fraction of ionic monomer can range from about 0.10 to about 1. Other polymeric architectures, such as block, star and graft, and gradient copolymers, they can also be advantageous. It is known that block copolymers are grouped into micelles and these micelles can be crosslinked in the core or envelope domain. Said segmented architectures can be produced by means of living free radical polymerization methods, such as RAFT or ATRP. When soluble polymers are used, the molecular weight is preferably between about 5000 g / mol and about 5,000,000 g / mol, and preferably between about 50,000 g / mol and 1,000,000 g / mol. When star-type or micellar-type polymers are used, the molecular weights are typically between 50,000 and 100,000,000 g / mol. Finally, when the polymers are crosslinked, the molecular weight is by definition infinite. The crosslinked polymers, used in accordance with the various embodiments of the invention, can take various formats, including globules with diameters ranging from about 10 nanometers to several hundred microns. Synthesis of core-shell compositions Some examples of processes that can be used to synthesize suitable core-shell compositions are the reverse suspension process and the direct suspension process. In the reverse suspension process, the hydrophilic core can be produced by reverse free radical polymerization using a block copolymer as a surfactant. Suitable monomers include vinylsulfonate, maleic acid, vinylphosphonate, vinyl bis phosphonate, acrylic acid, a-fluoroacrylic acid, styrene sulfonate and acrylamido-methylpropanesulfonic acid (AMPS) or their salts. The shell can be produced by a block copolymer in which one block comprises the wrapping material (eg, cationic and hydrophobic) and the other block is soluble and coreactive with the core polymer. Additional techniques for the synthesis of core-shell compositions are described in the co-pending patent application entitled "Ion-setting compositions", attorney's file number: 29329-715.201; filed on March 30, 2004, application number: 10 / 814,749. A useful process is to convert sulfonic monomers to their ester forms, which then become much less soluble in water and therefore are prone to direct polymerization in miniemulsion. The wrap can be produced by the addition of a second stage monomer to encapsulate the core. The final material is hydrolyzed under acidic conditions. In one embodiment, the wrapping material is designed to interact with bile acids and / or fatty acids, preferably irreversibly. Suitable bile acid binders that can be used in the wrap include cholestyramine, Welchol and the suitable compositions disclosed in U.S. Pat. 5633344, Macromolecules, 1997, 30, 6174-84, and J. Pharma Sci. 86, 1, 1997. An example of a suitable monomer that can be used in the core is 11-trimethylammonioundecylmethacrylate.

Another useful process comprises first forming an amine functional polymer, such as polyallylamine, polyvinylamine or polyethylene imine, and then treating it with a sulfonating agent, such as S03 / trimethylamine, or alternatively with a phosphonating agent, such as P205. Other polymer precursors can also be used, eg. , polystyrene, polybutadiene, polyisoprene, polypropylene, EPDM rubber and other similar precursors. In another process, highly-sulfonated or highly-phosphonated polymers are obtained from functional polymers of amines, which are subsequently reacted with vinylsulfonic, vinylphosphonic or vinyldiphosphonic acid through Michael additions.

Treatment of ionic imbalances and fluid overload The present invention includes methods of treatment using the polymers described above. The sodium-binding polymeric compositions and the sodium-binding core-shell compositions described herein can be used to treat diseases in which a reduction of the physiological levels of salt and / or water is desired. Patient populations in which the compositions and methods described herein are particularly useful include, but are not limited to, patients with congestive heart failure, hypertension, diabetes, chronic renal failure, end-stage renal disease, and liver cirrhosis. . In addition, suitable patient populations include patients suffering from fluid overload and / or salt overload. Another suitable patient population includes patients who are resistant to diuretic therapy and who suffer from hypertension, chronic heart failure, end-stage renal disease, liver cirrhosis, chronic renal failure, fluid overload, or a combination thereof. The compositions described herein are also useful in the treatment of peripheral edema, including premenstrual and mixed-type edema, and edema of pregnancy with or without hypertension, including preeclampsia. In one embodiment, patients treated with the compositions described herein benefit from the elimination of small amounts of salt constantly over a prolonged period of time. In another embodiment, patients benefit from the elimination of extracellular water and therefore have a beneficial effect on fluid control, blood pressure control, interdialytic weight gain and other aspects commonly related to fluid overload. when suffering from hypertension, chronic heart failure, end-stage renal disease, liver cirrhosis and / or chronic renal failure. In yet another embodiment, in patients suffering from end-stage nephropathy and chronic renal failure, the elimination of both sodium and chloride helps to control acidosis. The use of the compositions described herein can prevent the formation of edema after a cardiac episode in a patient. In addition, the compositions are suitable for the treatment of patients suffering from diastolic heart failure sensitive to volume / salt. In patients with end-stage renal nephropathy, the compositions of the present invention cause the elimination of sodium and therefore can cause a reduction in fluid overload. The elimination of sodium helps keep blood volume under control to treat hypertension. Treatment with the compositions of the present invention can produce a reduction in dosage and / or replace current treatments for hypertension, such as calcium channel blockers, and minimize weight gains per water between dialysis sessions that can have a significant impact on the heart, the duration of dialysis and the overall quality of life.

The polymers of the present invention are also useful in the treatment of patients with diabetic and hypertensive nephropathy. Typically, these patients develop resistance to diuretic therapy due to decreased renal function. In this patient population, the polymers of the present invention cause the elimination of sodium, which in turn allows to reduce hypertension and preserve renal function. The polymers can be used alone or in combination with vasotors. The compositions of the present invention can also be used to treat patients with hypertension. Other patients who may benefit from treatment with the compositions of the present invention include patients suffering from chronic heart failure, diarrhea, incontinence and liver cirrhosis. The term "treat" and its grammatical equivalents, as used herein, include achieving a therapeutic benefit and / or prophylactic benefit. With therapeutic benefit it is meant eradication or improvement of the underlying disorder that is being treated. For example, in a patient with hypertension, the therapeutic benefit includes the eradication or improvement of underlying hypertension. In addition, a therapeutic benefit is achieved with the eradication or improvement of one or more of the physiological symptoms associated with the underlying disorder, so that improvement is observed in the patient, regardless of whether the patient may still be affected with the underlying disorder . For example, administration of a polymer of the present invention to a patient suffering from hypertension provides therapeutic benefit not only when the patient's blood pressure is lowered, but also when an improvement in the patient is observed with respect to other symptoms accompanying the patient. hypertension, such as headaches. To achieve a prophylactic benefit, a polymer may be administered to a patient at risk of developing hypertension or to a patient exhibiting one or more of the physiological symptoms of hypertension, even if the diagnosis of hypertension has not been made. The present invention also includes kits comprising the compositions described herein. These kits comprise at least one of the compositions of the present invention and instructions that teach how to use the kit according to the various methods described herein. Combination Therapies In all suitable patient populations, the polymeric compositions of the present invention can be co-administered with other treatments. For example, the compositions can be administered with other standard treatments for hypertension and congestive heart failure. In patients with hypertension, polymers can be co-administered with standard therapy for hypertension, including, but not limited to, calcium channel blockers, diuretics, beta-blockers, alpha-blockers, medications for anxiety, ACE inhibitors, vasodilators and blockers of angiotensin II receptors. In this document, "co-administration" means simultaneous administration of the therapeutic agents in the same dosage form, simultaneous administration in separate dosage forms and separate administration of the therapeutic agents. For example, a polymer of the present invention can be administered simultaneously with a diuretic, where both the polymer and the diuretic are formulated together in the same tablet. Alternatively, the polymer could be administered simultaneously with the diuretic, where both the polymer and the diuretic are present in two separate tablets. In another alternative, the polymer could be administered first, followed by the administration of the diuretic, or vice versa. In one embodiment, the compositions described herein are co-administered with a laxative. Formulations and routes of administration The polymeric compositions and core-shell compositions described herein or the pharmaceutically acceptable salts thereof can be administered to the patient using a wide variety of routes or modes of administration. The most preferred routes for administration are oral or intestinal. The term "pharmaceutically acceptable salt" refers to those salts which retain the efficacy and biological properties of the polymers used in the present invention, and which are not undesirable either biologically or in any other way. Said salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, if the polymers used in the present invention contain a carboxyl group or other acid group, it can be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine. If necessary, the polymers and core-shell compositions can be administered in combination with other therapeutic agents. The choice of the therapeutic agents that can be co-administered with the compounds of the invention will depend, in part, on the condition being treated. The polymers (or the pharmaceutically acceptable salts thereof) may be administered per se or in the form of a pharmaceutical composition in which the active compound or compounds are an aggregate or a mixture with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds to form preparations that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration. For oral administration, the compounds can be formulated easily by combining the active compound or compound with pharmaceutically acceptable carriers well known in the art. Said carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, emulsions, suspensions, wafers and similar pharmaceutical presentations, for oral ingestion by a patient in order to receive treatment . In one embodiment, the oral administration formulation has no enteric coating. Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture and processing the granule mixture, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol, and cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, starch potato, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or mixtures of suitable solvents. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

For oral administration, the compounds can be formulated as a sustained release preparation. Numerous techniques for formulating sustained release preparations are known in the art. Pharmaceutical preparations that can be used for oral administration include snap-on capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Snap-fit capsules may contain the active ingredients in aggregate form with fillers, such as lactose, fixatives, such as starches, and / or lubricants, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should contain doses suitable for administration. Effective Dosages Pharmaceutical compositions suitable for use in the present invention include compositions in which the sodium-binding polymers are present in an effective amount, that is, in an amount effective to achieve a therapeutic and / or prophylactic benefit. The actual effective amount for a specific application will depend on the condition being treated and the route of administration. The determination of an effective amount is clearly within the capabilities of the people who master the technique, especially in view of the disclosure presented in this document. The effective amount for use in humans can be determined from animal models. For example, a dose can be formulated for humans to achieve gastrointestinal concentrations that have been found to be effective in animals. A skilled person who uses techniques known in the art can determine the effective amount of the polymer. In one embodiment, an effective amount of sodium fixative polymer is the amount that will reduce the diastolic and / or systolic pressure in a patient with hypertension, and preferably will reduce the blood pressure to a normal range. In some embodiments, the reduction is from about 20% to about 40%. The effective amount may also be an amount that increases the faecal excretion of sodium. An increase in sodium excretion from about 10 to about 150 mmol per day is preferred, an increase from about 20 mmol to about 100 mmol per day is even more preferred, and an increase from about 40 mmol to about 80 mmol is most preferred. per day.

EXAMPLES EXAMPLE 1 Measurement of the in vitro binding capacity of sodium The resin material is treated with 1 M HCl and washed repeatedly with water. Next, an aliquot quantity that has been weighed is titrated with 0.1 M NaOH and the capacity is recorded as the molar amount of base necessary to reach the desired pH (generally 6). Alternatively, the resin is soaked in a 1 M NaCl solution buffered to the desired pH, washed with water and finally treated with 0.5 M KCl. Then, the sodium released is titrated by ion exchange chromatography and the capacity of Sodium fixation is calculated accordingly. The polymer beads described in the examples that follow give typically a Na binding capacity in the range of about 6 to 10 mmol / g. EXAMPLE 2 Synthesis of sodium-binding polymeric compositions A. Synthesis of polyvinyl sulphonate polymer beads The vinyl sulfonate monomer is first polymerized in water with sodium persulfate as a free radical initiator in a pressure-proof reactor at 110 ° C. The oligomers of polyvinylsulfonate are isolated by precipitation in acetone. Next, the oligomers are treated with thionyl chloride to form copolymers of vinyl sulfonate-co- (vinylsulfonyl chloride). The beads are obtained by dispersing a solution of vinyl sulfonate-co- (vinylsulfonyl chloride) oligomers in toluene and then adding diaminopropane to form the desired beads. The final beads are washed extensively with water, 1 M HCl and water successively.

B. Synthesis of polyvinyl sulfamate polymer beads by reverse suspension polymerization 100 parts of vinylformamide / methylene bis-acrylamide in a weight ratio of 90/10 are solubilized in 100 parts of water with 1 part of sodium persulfate as initiator; then, the mixture is dispersed in 200 parts of toluene and one part of sorbitol sesquioleate as a surfactant, using a high shear homogenizer. The emulsion is maintained under mechanical stirring at 80 ° C for 8 hours. Then, the beads are filtered, washed with acetone and hydrolyzed in 1 M HCl for 6 hours at 50 ° C to obtain crosslinked polyvinylamine beads. Next, the beads are treated with trimethylamine / S03 to give the desired polyvinyl sulfamate particles. C. Synthesis of polyvinyl sulfamate / vinyl sulfate copolymer beads. The above process is repeated (Example 2B), except that 30 mol% of vinylformamide is replaced with vinylacetate.

D. Synthesis of polyvinylphosphoramide polymer beads The above process is repeated (Example 2B), except that the polyvinylamine groups are treated with P205. E. Synthesis of N- (bis-phosphoni-ethyl) polyvinylamine globules The above process is repeated (Example 2B), except that the polyvinylamine groups are further treated with diethylvinylphosphonate and the resulting polymer is hydrolyzed to the phosphonic form. F. Synthesis of poly-a-fluoroacrylic acid globules First, a-fluoroacrylic acid is prepared from chloroacetate ester and KF, following the procedure described in Pittman, CU, M. Ueda, et al., (1980), Macromolecules. 13 (5): 1031-1036. The globules are prepared by a direct suspension process in which a mixture of methyl a-fluoroacrylic ester / divinylbenzene / benzoyl peroxide in a weight ratio of 90/9/1 is dispersed in water under high shear with hydroxyethylcellulose as the active agent. suspension. The suspension is stirred and heated at 80 ° C for 10 hours. The residual monomer is removed by steam extraction. Next, the beads are filtered and treated with HCl to hydrolyze the polymer in order to form the desired poly-a-fluoroacrylic acid particles. G. Nuclear particles of (poly-a-fluoroacrylic acid) / envelope; (poly-11-trimethylammonioundecyl methacrylate) Cross-linked methyl a-fluoroacrylic ester polymer particles are prepared by mini-emulsion polymerization. A mixture of methyl a-fluoroacrylic ester / ethylene glycol dimethacrylate / AIBN / hexadecanol in a weight ratio of 88/9/1/2 in 0.5% by weight aqueous SDS solution is dispersed using a high Ultra-Turrax homogenizer. shearing. The temperature is set at 85 ° C for 15 hours and then at 75 ° C for another 5 hours, and a second stage monomer mixture composed of 25 parts of 11-dimethylaminodecylmethacrylate and 5 parts of divinylbenzene together with 5 parts of 5% by weight aqueous solution of sodium persulfate. Next, the dispersion is cooled to room temperature and treated with dimethyl sulfate to convert the diamino groups to trimethylammonium sulfate groups. The suspension is further treated with HCl to convert the methyl ester of the nucleus to the desired acid units. The average diameter of the particles is measured in a Malvern apparatus to determine the size of the particles by laser diffraction, obtaining a result of 0.5 microns.

H. Synthesis of vinylphosphonate / acrylic acid copolymer beads First, 50% by weight vinylphosphonate and acrylic acid are neutralized with NaOH to form a 50% by weight aqueous solution; 10% by weight of methylene-bis-acrylamide is added to this mixture with respect to the monomers. Next, 100 parts of that monomer mixture are emulsified in 200 parts of hexane and 1 part of sorbitan sesquioleate as the surfactant. 10 parts of a 5% by weight aqueous solution of sodium persulfate are added additionally to the suspension. The reaction is maintained at 80 degrees C for 10 hours, while adding 10 parts of sodium persulfate solution. The water is then removed by a Dean-Stark apparatus and the beads are filtered and washed repeatedly with methanol and water in this order. I. Synthesis of vinylphosphonate / acid copolymer globules. D-fluoroacrylic The process described in Example 2H is repeated, except that the acrylic acid is replaced with D-fluoroacrylic acid J. Synthesis of polyvinyl sulfate globules The crosslinked polyvinylacetate beads are prepared by direct suspension polymerization, filtered and they are hydrolyzed to obtain globules of polyvinyl alcohol by means of basic hydrolysis in methanol / NaOH. After extensive washing, the beads are further treated with sulfur trioxide / trimethylamine to give the desired polyvinyl sulfate particles. K. Synthesis of (polyvinylphosphonate / acrylic acid) shell / (styrene-vinylpyridine) shell using a block copolymer approach A diblock copolymer comprising a polyethylacrylate block and a second block of a styrene / 4 copolymer is prepared -vinylpyridine in a weight ratio of 50:50; the block ratio is chosen as 1: 1.5 and the total molecular weight is 50,000 g / mol. Next, an emulsion process is carried out in which 1 part of block copolymer is solubilized in 100 parts of deionized water, to which 20 parts of a mixture composed of terbutyl acrylate, ethylvinylphosphonate, ethylene glycol dimethacrylate and benzoyl peroxide in a weight ratio of 78: 18: 3: 1. The temperature is raised to 70 ° C and the reaction is allowed to proceed for 10 hours. The residual monomers are removed with a Dean-Stark device and the particles are then boiled in 1 M HCl overnight, neutralized with NaOH, washed with water and finally reacted with dilute HCl to give the core particles. -Wind desired. L. Preparation of core-shell particles comprising a cross-linked polyvinyl sulfamate core and a coating of 11-dimethylaminodecylmethacrylate / lauryl methacrylate copolymer The shell polymer is prepared separately by free radical polymerization of a monomer mixture of 11- dimethylaminodecylmethacrylate / lauryl methacrylate with a weight ratio of 50:50 in 20% by weight in DMF, using AIBN as initiator. The pellets obtained in Example 2B are spray coated with the aforementioned polymeric wrapping solution using a portable 2"- 4" / 6"Wurster fluid bed coater unit.The fluidized bed unit is operated in such a way that a coating of 5 microns of average thickness is deposited on the core particles M. Core-shell particles using a latex deposition process The shell polymer is prepared as an emulsion using direct emulsification techniques or emulsion polymerization. The pellets are then contacted with the latex for a given period of time, decanted and spray dried, higher rates of deposition in the envelope are achieved by inducing the latex coagulation of the latex on the core globules by means of a change in temperature, adding electrolyte, varying the pH or using a combination of these procedures. Core-shell particles prepared from poly-D-acrylic acid core particles and multi-layer polyallylamine / polystyrene sulfonate shell. First, the negatively charged core globules of Example 21 are suspended in a dilute aqueous solution of poly (allylamine hydrochloride) at room temperature for 20 minutes, then the beads are separated from the solution by centrifugation and subsequently washed with water. Next, the beads are suspended in a dilute aqueous solution of sodium polystyrene sulfonate for 20 minutes, separated by centrifugation and washed with water. This process is repeated until an envelope of 20 nm thickness is obtained. O. Polyacrylic acid / lactose-containing core globules containing lactose A lactose styrene derivative (glyomomonomer) is prepared according to the procedure described by Kobayashi et al., Macromolecules, 1997, 30, 2016-2020. A glycopolymer is prepared by copolymerization of glyomomonomer, glycidyl methacrylate and butylacrylate in DMF, using AIBN as initiator. The glycopolymer is attached to the poly (acrylic acid) beads by suspending the beads in glycopolymer solution in DMF at 60 ° C for 8 hours and the core-shell beads are isolated by centrifugation and washed with DMF and water. EXAMPLE 3 Measurement of sodium binding capacity under physiological conditions representative of the upper Gl tract The particles of Examples 2A-20 are conditioned under the proton form and added to a reconstituted Gl fluid representative of the segment of the jejunum, including bile acids, Fatty acids and intestinal enzymes. The Na and K cations are adjusted to 80 mM and 15 mM, respectively. After an incubation at 37 ° C for 30 minutes, the beads are isolated by filtration and washed with deionized water. Then, a solution of 0.5 M LiCl is added to displace the cations of both Na and K. Then, the cation fixing capacity is calculated and it is found to be in the range of 3 mmol / g to 10 mmol / g to sodium and from 0.2 mmol / g to 2 mmol / g for potassium.

Measurement of the sodium binding capacity under physiological conditions representative of the lower Gl tract The particles of Examples 2A-20 are incubated in the liquid of the simulated upper tract, isolated and washed as indicated above, and then they add to a simulated fluid representative of the environment of the colon, where the concentrations of potassium and sodium ions are adjusted to 70 mM and 0 mM. After a 30 minute incubation, the particles are centrifuged, the supernatant is subjected to tests to determine the Na amount released from the bead and the resulting Na binding capacity is calculated. A comparative example is carried out with a commercial polystyrene sulfonate resin in acid form with a nominal capacity of 5 mmol / g. All particles of the present invention show superior Na binding in the simulated liquids of the upper and lower tract. EXAMPLE 4 Animal model to demonstrate the non-absorbed nature of the Na-fixing resin These studies are carried out using the administration of a single resin bolus labeled with 3 H or 14 C, which is given to rats housed in metabolic chambers. The study design consists of two groups of six Sprague-Dawley rats; animals in group 1 receive a single oral dose of radiolabelled resin (250 mg / kg body weight), while group 2 animals are pretreated with unlabeled resin in the diet at doses of ~ 6 g / kg / day during 28 days, followed by a single administration of resin labeled on day 29 (250 mg / kg body weight). Group 1 is used to measure absorbance and elimination in animals that have not previously been treated with resins, while Group 2 is used to monitor absorbance and elimination in chronically treated animals, as it could be seen in patients They take the resin daily. The urine and total faeces are collected and analyzed for the presence of radiolabel after 0, 6, 12, 18, 24, 48 and 72 hours after the administration of the labeled resin. At the time of sacrifice, aliquots of blood are taken and plasma is harvested by centrifugation; The content of the Gl tract is collected and tissue samples are collected from the stomach, small intestine, small intestine, large intestine, rectum, liver, spleen, skeletal muscle and lymph nodes. The weights of urine, tissues and Gl content are determined and the tissue is ground. The radioactivity present in the urine and in the plasma is determined by liquid scintillation counting. The fecal tissue and whole blood homogenates are divided into aliquots and combusted, and the radioactivity trapped in the aqueous phase is determined by liquid scintillation counting. The properties of a non-absorbed resin are: (i) absence of significant urinary excretion of radioactivity (< 0.05% of the dose for both groups), (ii) total mean radioactivity excreted in the faeces between 97% and 100% of the tdtal dose for arabos groups, recovered within the 72-hour collection period; (iii) blood, plasma, liver, kidney, spleen, skeletal muscle and lymph nodes (ie non-gastrointestinal tissues) have < 0.07% of the total labeled resin dose at the collection point after 72 hours; and (iv) the stomach, small intestine, large intestine, caecum, and rectum have < 0.1% of the total dose of labeled resin at the collection point after 72 hours. EXAMPLE 5 Studies in human volunteers to demonstrate the non-absorbed nature of the Na-fixing resin. A resin labeled with 14C is prepared to give about 0.2 mCi / g of resin. In a typical study design, 20 volunteers receive 3 capsules of 600 mg unlabeled resin three times a day for 28 days (total daily dose = 5400 mg). Sixteen patients are admitted to the metabolic unit of clinical research at a designated center, to continue with the radiolabel part of the study. On the morning of the first day of confinement, patients receive a single oral dose of 2.4 g (4 capsules of 600 mg) of resin labeled with 14 C up to a total of 480 μCi of 14C per patient. Next, unlabeled resin is administered in the same manner as before for the next three days. Blood samples are drawn after 0, 4, 8, 12, 24, 48, 72 and 96 hours. The urine and faeces evacuated in the initial moment are collected along intervals of 0-24 h, 24-48 h, 48-72 h and 72-96 h. Fecal homogenates and whole blood samples are dried and oxidized before scintillation counting. Radioactivity in blood, urine and faeces is expressed as a percentage of the dose administered for each time interval and as a total percentage. The properties of a non-absorbed resin are: (i) there are no detectable amounts of 14 C-labeled resin in the whole blood of any patient at any time during the study; (ii) for each patient, < 0.009% of the dose of labeled resin in the collected urine samples, covering the 96-hour period following the administration of the labeled resin; and (iii) for each patient, > 99% of the dose is recovered in the stool over a period of 10 days after the administration of the resin marked with 14C. EXAMPLE 6 Animal models to demonstrate the Na-binding capacity of the resins Animal models are used to demonstrate the binding of sodium cations by the resins, which are added as a supplement to a controlled diet that is administered to rats or dogs. Generally, these studies are performed in normal animals to demonstrate an effect of the resin and then in models with sick animals in which a sustained imbalance of electrolytes is created that produces extravascular edema, which is achieved by affecting renal, hepatic or cardiac function of the test animal. A typical experiment with normal rats to determine the relative binding efficiency of the test polymers uses three groups (n = 6 / group) of female Sprague-Dawley rats placed in individual metabolic cages with a diet consisting of low sodium biscuits and water distilled Sodium is administered daily by means of an oral feeding tube in three doses as a 200 mM solution (2.4 meq). During the first three days of the test, initial data are collected in the form of meq / day of sodium in the urine and meq / day of sodium in the stool; The usual measurements of sodium are 2.25-2.5 meq / day in the urine and 0.05-0.3 meq / day in the stool. Over the next three days, the three groups of test animals receive fixed doses of the test resin (500, 1000 and 2000 mg / kg / d) in addition to the saline solution administered orally in three doses. In the final three days of the test, the resin is removed from the oral probe and the saline solution is administered in the same manner as in the first period, to provide a second monitoring control period. Active resins are those that reduce the sodium content in the urine during the second administration period below 2.25 meq / day (typical intervals are 0.25 to 1.5 meq / day) and increase the sodium content in the faeces ( Typical values range from 2 meq / g to 5 meq / g resin). The content of sodium in urine and feces is determined by extraction and ion exchange chromatography or by flame photometry. A typical experiment with rats that have impaired renal function, used to simulate hypertension and fluid retention in the patient with end-stage renal disease, uses chemical induction of kidney damage (uranyl acetate, gentamicin, cephaloradin, etc.) or surgical resection of the kidney (nephrectomy 5/6) to induce chronic renal failure. After the chemical or surgical manipulation of the animals and the stabilization of the renal function in a reduced state, the animals are divided into three test groups (n = 10 / group). As in the tests with normal animals, the test animals are kept for 3 days with low sodium biscuits and receive a solution of 75 mM NaCl ad lib; the initial values of sodium for urine and faeces are determined. Then, the animals of each group are given fixed amounts of the resin by oral gavage (3 doses, with total daily doses of 500, 1000 and 2000 mg / kg / d) for three days, with a period of "elimination". "Three days after the administration of the resin. Sodium in urine and faeces is determined throughout the periods of initiation, testing, and elimination-generally, the sodium content in the urine is high in the periods of onset and elimination (4-5). meq / d), but it is reduced in the treatment phase (1-2 meq / d). Similarly, the fecal sodium in the initial and elimination groups is 0.03-0.5 meq / d and increases to 3.8-5 meq / g of resin in the treated animals. EXAMPLE 7 Studies in human volunteers to demonstrate the capacity of sodium fixation of resins The completion of safety pharmacological and toxicological analyzes of resins conferring them the category of new experimental drug will allow studies with human volunteers in normal patients, for evaluate the in vivo binding capacity of the test resins. The design of a typical study enrolls 24 normal patients housed in a clinical metabolic unit; patients have a normal body weight, give normal results in hematological and chemical tests, and have no history of Gl, renal or hepatic diseases. After the selection, volunteers are randomly assigned to 3 groups of 8 patients each; Six of the patients in each group are randomized to receive a specific dose of resin (25 mg / kg, 70 mg / kg, 140 mg / kg) and two to receive placebo. The volunteers are housed in the metabolic unit for 18 days and consume a diet with the controlled sodium of 5 g of elemental sodium per day (3 meals and 1 snack). The design of the study is as follows; On day 1, patients receive a single oral dose of resin or placebo according to the treatment group. During the following seven days (d2-d8), patients do not receive drug; From the morning of day 5 until the morning of day 9, 24 hours of urine and faeces are collected and the sodium and potassium content of the samples are determined. On days 9 to 16, all patients receive the same dose according to the group, with doses divided among three daily doses; urine and total faeces are collected from day 13 to day 17. Patients are discharged on day 18. The fecal sodium content is high in the treatment groups, approaching 4-5 meq / g of resin .

EXAMPLE 8 Membrane activated by pH Membranes were synthesized with copolymers of dibutylacrylamide and dimethylaminoethyl methacrylate and their permeability profiles at different pH were evaluated. The donor solution used to study the permeability was buffer of Na + 50 mM at different pH. The results are shown in Figure 2. With the increase in pH (pH range of 5 to 8), the permeability of the membrane decreased and the membrane became even impermeable to high pH. The composition of the membrane also affected permeability. For samples with DBA < 50% (D2, D3), the membrane was impermeable to high pH (> 7.5).

All publications and patent applications mentioned in this specification are hereby incorporated by reference, with the same scope as if each publication or individual patent application was specifically and individually indicated to be incorporated by reference. For a person having ordinary skill in the art, it will be evident that many changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (44)

1. CLAIMS: 1. A method for removing sodium from an animal patient, comprising administering to an animal patient in need thereof, an effective amount of a sodium-binding composition comprising a sodium-binding polymer, wherein said polymer has a Sodium binding capacity in vivo of 4 mmol or more per gram of said polymer in a human. The method of claim 1, wherein said sodium fixing composition retains a sodium fixed in a lower gastrointestinal tract. The method of claim 2, wherein said sodium fixing composition exhibits a reduction in permeability to said sodium fixed in said lower gastrointestinal tract. The method of claim 1, wherein said sodium binding composition retains a significant amount of a sodium fixed in an environment comprising a NaMK + concentration ratio of 1: 4. The method of claim 1, wherein said sodium binding composition is swollen in an isotonic liquid environment. The method of claim 2, wherein said sodium fixation and / or sodium retention by said sodium binding composition depends on a pH of an environment surrounding said polymer composition. The method of claim 2, wherein said sodium fixation and / or sodium retention by said sodium binding composition depends on a concentration of bile acids and / or fatty acids in an environment surrounding said polymer composition. The method of claim 2, wherein said sodium fixation and / or sodium retention by said sodium binding composition depends on an activity of the enteric enzymes in an environment surrounding said polymeric composition. The method of claim 1, wherein said sodium fixing composition comprises sulfonate or phosphonic polymers. The method of claim 1, wherein said sodium fixing composition does not release harmful ions. The method of claim 10, wherein said noxious ion is at least one of the following ions: K +, Cl ", OH" or Ca2M 12. A method for removing sodium from an animal patient, comprising administration, to an animal patient in need thereof, of an effective amount of a sodium fixing composition comprising an acid resin, wherein said resin has an in vivo sodium binding capacity of 4 mmol or more per gram of said resin in a human and said composition retains a sodium fixed in a lower gastrointestinal tract. The method of claim 12, wherein said acid resin comprises repeating units charged with H + ions or NHM 14. The method of claim 1 or 12, wherein said effective amount of sodium binding composition administered It is not more than about 15 g per day. 15. The method of claims 1 or 12, wherein said sodium fixing composition removes approximately 50 mmol of sodium per day. 16. The method of claim 1 or 12, wherein said sodium fixing composition comprises at least one of the following polymers: polyvinyl sulfonate polymer, polyvinyl sulphamate polymer, polyvinyl sulfamate / vinyl sulfate copolymer, polyvinyl phosphoramide polymer, N- polymer ( bis-phosphoni-ethyl) polyvinylamine, poly-a-fluoroacrylic acid polymer, vinylphosphonate / acrylic acid copolymer, vinylphosphonate copolymer. / a-fluoroacrylic acid, polyvinyl sulfate polymer, cross-linked polyvinyl sulfamate polymer or poly-acrylic acid polymer. A method for removing sodium from an animal patient, comprising administering, to an animal patient in need thereof, an effective amount of a core-shell composition comprising a cation exchanger core and a semipermeable envelope, wherein said The cation exchange nucleus is capable of fixing sodium in an upper gastrointestinal tract and the semipermeable envelope is characterized by a decrease in the permeability to sodium fixed in a lower gastrointestinal tract. 18. The method of claim 17, wherein the core has an in vivo sodium binding capacity of 4 mmol or more per gram of said resin in a human. The method of claim 17, wherein said core binds more sodium in said upper gastrointestinal tract in the presence of said wrapping component compared to the amount of sodium fixed by said core in the absence of said wrapping component. 20. The method of claim 17, wherein said semipermeable envelope preferentially binds chloride. The method of claim 17, wherein said semipermeable envelope prevents entry of competing solutes. 22. The method of claim 17, wherein said competing solute is at least one of the following: K +, Mg ++, Ca ++, NH4 +, H + or protonated amines. 23. The method of claim 21, wherein said semipermeable shell is permeable to sodium ions at a pH of about 1 to about 5. The method of claim 17, wherein said core preferentially binds sodium in said upper gastrointestinal tract and said semipermeable envelope is permeable to sodium ions at a pH of about 7 and above, and said permeability to the ions is reduced to a pH of from about 5 to about 6. The method of claim 17 , wherein said permeability of said semipermeable envelope is modulated by a binding of bile acids and / or fatty acids to said envelope. 26. The method of claim 17, wherein said permeability of said semipermeable envelope is modulated by enteric enzymes or enzymes produced by the colonic microflora. The method of claim 17, wherein said core comprises at least one of the following polymers: a polyvinyl sulfonate polymer, a polyvinyl sulfamate polymer, a polyvinyl sulfamate / vinyl sulfate copolymer, a polyvinyl phosphoramide polymer, a N- polymer ( bis-phosphoni-ethyl) polyvinylamine, a polymer of poly-a-fluoroacrylic acid, a copolymer of vinylphosphonate / acrylic acid, a copolymer of vinylphosphonate / a-fluoroacrylic acid, a polyvinyl sulfate polymer, a crosslinked polyvinyl sulfamate polymer or a polymer of poly-acrylic acid, and said casing comprises at least one of the following polymers: a polymer of poly-11-trimethylammonioundecylmethacrylate, a styrene-vinylpyridine polymer, a copolymer of 11-dimethylaminodecylmethacrylate / lauryl methacrylate or a polymer of polyallylamine / polystyrene sulfonate. A method for removing salt from an animal patient, comprising administering, to an animal patient in need thereof, an effective amount of a salt binding composition comprising a salt binding polymer, wherein said fixed salt fixing polymer chloride and sodium, and said composition retains the sodium fixed in a lower gastrointestinal tract. 29. The method of claim 28, wherein said polymer has an in vivo sodium binding capacity of 4 mmol or more per gram of said polymer in a human. 30. The method of claim 28, wherein said salt-binding composition is an internal salt of a polyelectrolyte complex, wherein said complex is prepared from polymers of opposite charges. 31. The method of claim 28, wherein said salt binding composition does not introduce harmful ions. 32. The method of claim 31, wherein said noxious ions are at least one of the following ions: K +, Cl ", OH" or Ca2M 33. The method of claim 28, wherein said dose of the polymer composition does not It is more than 10 g per day. 34. The method of claim 33, wherein said dose of the polymer composition removes approximately 3 g or more of salt per day. 35. The method of claim 1, 12, 17 or 28, wherein said animal patient suffers from hypertension, chronic heart failure, end-stage renal disease, cirrhosis of the liver, chronic renal failure, fluid overload or sodium overload. 36. The method of claim 35, wherein extracellular water is removed from said animal patient. 37. The method of claim 35, wherein a beneficial effect in fluid control, blood pressure control and / or interdialytic weight gain is observed. 38. The method of claim 1, 12, 17 or 28, wherein said animal patient suffers from a disease characterized by the presence of anomalous amounts of sodium and / or water in the body of said animal patient. 39. The method of claim 1, 12, 17 or 28, wherein said animal patient is resistant to treatment with diuretics and suffers from hypertension, chronic heart failure, end-stage renal disease, liver cirrhosis, chronic renal failure, fluid overload. or a combination thereof. 40. The method of claim 1, 12, 17 or 28, wherein a small amount of sodium is removed from the animal patient over a prolonged period of time. 41. The method of claim 1, 12, 17 or 28, wherein the treatment of said animal patient prevents the formation of edema after a cardiac episode. 42. The method of claim 1, 12, 17 or 28, wherein said animal patient suffers from volume / salt sensitive diastolic heart failure. 43. The method of claim 1, 12, 17 or 28, wherein said composition is coadministered with a diuretic, an ACE inhibitor, a α-blocker, a β-blocker, an angiotensin II receptor blocker, or a combination of them. 44. The method of claim 1, 12, 17 or 28, wherein said composition is coadministered with a laxative.