MXPA99003817A - Water-soluble polymers for the reduction of dietary phosphate or oxalate absorption - Google Patents

Abstract

The present invention is directed to a water-soluble polyether glycol polymer having:a structural backbone of carbon atoms and oxygen atoms where there are at least two consecutive carbon atoms present between each oxygen atom;a moiety on the backbone of the polymer or a functionalized derivative on the polymer, that is cationic at physiological pH and permits complexation with phosphate or oxalate;and an average molecular weight from about 5,000 to about 750,000 Daltons. These polymers are formulated for oral dosage to reduce the phosphonate or oxalate levels in an animal. The process of preparing these polymers and the method of reducing gastrointestinal absorption of phosphate and oxalate are included.

Description

SOLUBLE OLIMERS IN WATER FOR THE REDUCTION OF ABSORPTION OF PHOSPHATE OR DIETETIC OXALATO FIELD OF THE INVENTION The invention relates to a composition of matter comprising water soluble polymers capable of complexing the phosphate or oxalate processes to prepare the polymer processes for using the polymers in the complexation of dietary phosphate or oxalate in animals to prevent their absorption of the gastrointestinal tract and to formulations for use as non-systemic agents BACKGROUND AND COMPENDIUM OF THE INVENTION It is known that serum phosphate levels above the normal scale have detrimental effects Hyperphosphatemia the condition of having excessive levels of phosphate in the serum is has shown that it causes pathological conditions such as osteodystrophy and secondary hyperparathyroidism [see for example ME Rubín and others Arch Intern M? d 12 663669 (1969) and E Slatopolsky and others Kidney Int i 2 1 7 151 (1972)] The main group in risk of hyperphosphatemia are those patients who develop renal failure Their hyperphosphatemia is d It develops when your kidneys no longer work properly to excrete the phosphate consumed in your diet and results in many complications [See for example D Mizumoto and others Clin Nephrol 4¿ 315321 (1994) for details of the clinical source] The treatment of patients with chronic renal failure is very expensive and requires a lot of time of the professional doctor. Patients with renal failure can not excrete all the fluid sodium potassium chloride phosphate nitrogen and other minerals ingested in their diet and that are not necessary in the body. treatment for these patients progresses from minimal dietary restriction to severe dietary restriction to dialysis or peptoneal hemodiahsis depending on their level of renal impairment. Renal transplantation may be required for many patients but lack of adequate kidney donors may require the patient to undergo to hemodialysis for years before transplantation is possible Based on Medicare data approximately 150,000 patients currently receive hemodialysis in the United States In the stage of renal failure when dialysis is needed usually many metabolic imbalances are present Because the kidneys are no longer handle the load of f Fluid ingested and electrolytes need excretion total body levels of sodium potassium calcium phosphate chloride water and several trace minerals are usually higher than normal Retention of excess fluid and abnormal hormone production causes hypertension Metabolism causes hyperlipidemia and hypercholesterolemia Consistently patients who undergo renal dialysis usually receive numerous medications to control their blood pressure hormone status fat levels and serum chemists They usually must also endure severe dietary restrictions including minimum protein consumption, precise restriction of fluids, strict restriction of sodium, low fat intake and high consumption of simple carbohydrates. These dietary restrictions are necessarily due to the fact that renal dialysis is not efficient to restore the body's chemistry and the resulting hormonal levels to the body. Normal levels Dialysis often requires four to eight hours per session two to four times a week to remove the creatine urea fluid and the electrolytes generated even with the restricted diet. Phosphate is particularly difficult to control with dialysis since the phosphate is dialysis poorly with membranes commonly used for dialysis Other diseases in addition to renal failure cause hyperphosphatemia Primary hypoparathyroidism is a rare cause of hyperphosphatemia [See for example D Mizumoto and others Clin Nephrol 42. 315-321 (1994)] Phosphate poisoning can also be presented with the ad administration of oral purgative phosphate-containing enemas or urinary acidifiers Thyroid carcinoma occasionally results in hyperphosphatemia Rapid lysis of tumors during chemotherapy can also cause hyperphosphatemia which can form a renal compromise from the excessive acid produced by the tumor sis [See for example T Smith South Med J 8 ± 415416 (1988)] Hyperphosphatemia has also been reported in children and diabetic mothers [See for example RC Tsang and others J Pediatrics 89. 115 119 (1976)] Although it is much less common than renal failure These diseases also cause significant health problems. Therapy for these causes of hyperphosphatemia often includes dietary restriction of phosphate to decrease the amount of phosphate absorbed. Another state of illness that causes significant morbidity and expense is the formation of kidney stones. Kidney stones cause 400,000 hospitalizations in North America each year. Oxalate stones cause 234,000 of these hospitalizations. Some metabolic routes of mammals can result in the formation of oxalate, which can not be further metabolized and must be excreted through the kidneys. These routes, however, are less than a third of the urinary oxalate while the dietary oxalate is the source of 67% of the urinary oxalate in metabolically normal patients [See, for example, R.P. Holmes, and others, Scanning Microsco. 9: 1109-1120 (1995)]. The oxalate, both endogenous and dietary, must be excreted through the kidneys together with other substances such as calcium, excess hydrogen, urea and sodium. Calcium oxalate and oxalic acid have low solubility in urine and will easily precipitate to form kidney stones. Patients with steatorrhea, loyal resection, ileal shunt, severe ileal mucosal disease or pancreatic insufficiency, have greater dietary oxalate absorption than healthy persons and have more severe problems with oxalate stones [See J. Q. Stauffer, Am. J. Dig. Dis. 22: 921-928 (1977); A.F, Hofmann, et al., Int. J. Obes. 5 ^: 513-518 (1981); K. Dharmsathaphdrn, and others, Dig.

Dis Sci 21 401-405 (1982), Gastroenterology 84293-300 (1983), and DP D'Cruz et al., Br J Urol 64231-234 (1989)] Genetically, the hyperoxalupa determined causes the increased endogenous production of oxalate which can cause the formation of renal oxalate stones Dietary oxalate may exacerbate the formation of kidney stones in these patients Although current therapy for hyperphosphatemia emphasizes dietary restriction of phosphate to decrease phosphate loading it is often inadequate to fully treat hyperphosphatemia and is very problematic for patients Usually, it becomes necessary to supplement the dietary restriction with some therapy designed to prevent the ingested phosphate from being absorbed through the gastrointestinal tract [See, for example, JA Ramírez et al. Kidney Int'l 30, 753-759 (1986), and MS Sheikh and others J Clin Invest 83 66-73 (1989)] Similarly hyperoxalupa treatments have focused on the di Decrease dietary intake of oxalate by eliminating various foods or avoiding oxalate absorption from the gastrointestinal tract Dietary restrictions have been difficult and confusing Some authors suggest that all green vegetables rhubarb and chocolate should be avoided Other authors add beets cereal nuts wheat and strawberries to foods that should be restricted while allowing all green vegetables except spinach [See for example LK Massey and others J Am Diet Assoc 93 901-906 (1993)] Some authors suggest high calcium intake while others suggest strict calcium limitations Some authors require low protein diets while others insist that proteins have no participation in the treatment while dietary carbohydrates and fats should be kept at a minimum level suggested for oxalate have included calcium magnesium aluminum and fiber [See for example RP Holmes and others Scapnmg Microsco 9 1109-1120 (1995) and AF Hofmann and others Int J Obes 55135180 (1981)] Other authors point out that excessive calcium will lead to more Stone formation Some authors restrict fiber None of these regimens has been particularly successful as evidenced by the 50% recurrence rate of kidney stones within the first 6 years after the removal of a kidney stone. The preferred treatment could involve the binding of oxalate in the gastrointestinal tract by an agent that could prevent its absorption. The usual method to achieve this binding of both phosphate and oxalate involves the use of oxalate agents. complex formation "Complexing agents are compounds that attract other certain compounds and keep them in association with the complexing agent. Many different mechanisms can operate to attract a target molecule or an ion to a complexing agent. simple complex formation can be ions capable of reacting with a substance and form an insoluble compound that is then precipitated reaction of two ionic species to form an insoluble molecule is one of the simplest forms of complex formation "Chelators" are a type of complex formation agents that form complexes known as "chelates" Chelates form two or more covalent bonds coordinated with other compounds, ions or atoms through at least two sites in the formation agent of complexes These sites are often 'extensions' containing three to eight atoms, thus allowing the formation of a ring of four to ten atoms when the atom or complexed molecule is covalently bound to both ends of the chelating agent. Partially, due to this formation of the rings, the chelators are more stable than the compounds formed of the same two molecules only forming a coordinated covalent union The stability of the chelant is also improved when they react vain 'extensions', creating several rings In addition to the stability of the increasing number of rings, these compounds have increased stability from the steppe interaction of the di different extensions that surround the complexed or molecular atom thus avoiding the easy dissociation of the complex Other forms of compound formation agents that include those that attract and maintain the molecules through the ionic attraction The attraction of dipoio-dipole or dipole-ions also can be the source of the ability of complex formation agents to attract and maintain the complex complexed Other forces that may be involved to help complexing agents to function include hydrophobic and hydrophilic interactions These forces mentioned above are given as purely illustrative examples and are not intended to include all the forces through which the agents of Complex formation can attract and maintain the compounds Functionalized solid resins have been used to form complexes of several substances of biological interest This is illustrated by colestiramma, a polystyrene entangled with a portion of the styrene monomers functonalized with a quaternary amine chloride. resin attracts and maintains bile acids thus preventing their absorption from the gastrointestinal tract [See "Questran ™ Powder", by Bpstol-Meyers Squibb, Phvsicians Desk Reference. 51"Edition, 1997, p. 77-776] However, cholestaramine suffers from an unpleasant taste and low binding capacity. This requires patients to take large doses of an off-flavor solid which leads to poor patient compliance. cholestyramine exchanges its chloride with, and then binds to, the bile acid ion The amount of chloride released frequently enough to cause metabolic acidosis at doses of cholestyramine below those required to treat the patient properly These problems of gritty, unpleasant taste , low binding capacity and ion exchange of an undesirable amount of an ion of the Reams are common for most resins researched until now. Therapy with complexing agents for hyperphosphatemia in patients with renal failure has focused on the precipitation of phosphate in the gastrointestinal tract with aluminum or calcium salts. Aluminum salts (usually hydroxides, such as Amphojel ™ by Wyeth-Ayerst or Maalox ™ by Ciba) have been more successful because aluminum has been absorbed from the gastrointestinal tract and caused osteomalacia and neurological disease Calcium carbonate salt (Tums ™ by SmithKine) Beecham) has been the most widely used clinical agent although acetate (PhosLo ™ by Braintree), citrate and alginate salts have also been used. These agents result in excessive absorption of calcium with resulting soft tissue calcification. Calcium-hydroxy-β-methylbutyrate has been proposed as a phosphate complexing agent [See for example M F Sousa and others, Nephron 72 391-394 (1996)] This salt also works through the precipitation of calcium phosphate resulting in all the problems associated with the other calcium salts. It has been proposed for patients of renal hemodialysis mainly due to the fact that ß- hydroxy-ß-methylbutyrate is reported to improve protein metabolism Anion exchange resins have been purchased in vitro with Bio Rex ™ 5 aluminum salts Dowex ™ XF 43254 Dowex ™ XY 40012 and Dowex ™ XY 40013 all have Union of about half of the Dowex ™ SBR and Dowex ™ 1-X8 aluminum compounds could bind only one third of the phosphate that binds to the Dowex ™ XF 43311 aluminum salts and Dowex ™ XY 40011 could join 80% of the phosphate of what aluminum salts could be bound (all Dowex resins are by The Dow Chemical Company and strong base anion exchange resins based on quaternary amine functionality) [See for example HM Burt and other Uremia Invest 9 (1) 35-44 (1985-1986) and HM Burt and others J Pharm Sct 76 (5) 379-383 (1987)] These agents have not been used in patients since they release chloride which could cause acidosis requiring large doses to compensate for low binding capacity and bind to bile acids which could limit the allowable dose before it is present diarrhea from malabsorption of fats Other complexing agents for phosphate have been proposed These have included iron dextran salts crosslinked rare earth salts and zirconyl chloride [See for example K Spengler and other Nephrol Dial Transplant 1_1 808-812 (1996) and L Graff and others Res Commun Mol Pathol Pharmacol 90. 389-401 (1995)] Each of these agents is designed to complex phosphate by forming a precipitate between metals and phosphate. None of these agents have been administered to human volunteers or patients. The amount of activity to look for the formation agents of phosphate complexes witness the need a better method to treat hyperphosphatemia than currently available to dietary restriction or known and available medications Compendium of the Invention Surprisingly, it has now been found that, in contrast to water-insoluble resins and polymers to be used as in vivo phosphate or oxalate reduction agents, it is known that it is possible to use a water soluble glycol polyether polymer This polymer has a base structure of carbon atoms and oxygen atoms wherein at least two consecutive carbon atoms are present between each oxygen atom Examples of such polymers they include polyethylene glycols and polypropylene glycols. These polymers must be water soluble and have a portion of the polymer base structure or a functionalized derivative on the polymer that is cationic at physiological pH and allows complexation with phosphate or oxalate. These polymers have an average molecular weight of about 5,000 to about e 750000 Daltons These polymers are formulated in conventional forms and live m in an animal is used to reduce the amount of phosphonate or oxalate present. To prepare these polymers care must be taken to obtain the desired molecular weight and solubility so that these polymers with They are frequently functionalized with derivatives Detailed Description of the Invention Accordingly, the present invention relates to a series of water-soluble polyether glycols (PEG) which are capable of avoid problems with current and proposed phosphate or oxalate complexing agents PEG includes polyetihalohydrin polymers (PEi) wherein the halo portion of the PEi polymer can be chloride bromide iodide Polyether glycols (PEi) have a structure of the carbon and oxygen structural base where the number of consecutive carbon atoms must be two or more and there are no consecutive oxygen atoms Examples of these polyether glycols are polyethylene ghcol and propylene glycol The solubility in water of these PEG polymers present that are usually derivatives leads to a homogeneous mixture with the biological fluids being treated in the animal (this means warm-blooded mammals including humans) instead of the slurry of a resin insoluble in biological fluids as is known by the present methods It has discovered that this solubility results in improved mixing and improved complex formation which allows lower doses of the complexing agent to be used. Furthermore, the administration of the agent is more pleasant to the animal since the granular texture is not present and since the The flavor of the agent is diminished and can be more fully framed with an aqueous taste of what the resin could be. The formulation that can be used with the polymers of PEG-D (derivatives of gf i col of polyether) especially the polymers of PEi-D It is for non-systemic use Therefore these formulations are administered orally to the animal The dose of the PEG-D polymer It is done by the amount of phosphate and oxalate that must be removed. An orally given phosphate binder could be dosed according to a ratio of the binding site on the polymer to phosphate in the diet. The normal American diet has 48 to 65 mmol of phosphorus per day. A 1X charge could be one mole of polymer binding sites per mole of dietary phosphate. A 5X load could be 5 moles of polymer binding sites per mole of dietary phosphate. PEi / TMA (14,000 Mp) at pH 7, in saline and with a 5X load of 0.69 mmol of phosphate absorbed by the polymer per gram, binding of approximately 98% of the phosphate. To absorb 48 to 65 mmoles of phosphate, 70 to 94 grams of this polymer per day may be required. PEi / EDA (approximately 14,000 to 20,000 Mp) at pH7, in saline and with a 5X load of 1.38 to 1.73 mmoles of phosphate absorbed by the polymer per gram (approximately 98% of the phosphate) and could require from 28 to 47 grams per day to join phosphate in the diet. In the rat tests, a 1X load was very effective in decreasing serum phosphate within one or two weeks. A dose of 2X decreased serum phosphate faster. A dose of 5X decreases serum phosphate in a few days, but the rats were not fed normally, so some of the phosphate decrease may have been the result of famine. From the analyzes with rats, it might seem that a usual dose would be from a load of O 5X to 1 Xx while doses as high as 5X could be used for one or two days to decrease phosphate more quickly. Therefore the usual dose could be from about 3 to about 10 grams per day ( or about 1 to about 3 grams per meal 3 meals per day) and the short-term dosage could be as high as about 15 to about 50 grams per day (or about 5 to 16 grams per meal 3 meals per day) Therefore the effective amount of PEG-D or PEi-D is about 1 to about 15 grams per meal to remove phosphate from the diet. The normal American diet varies from 0 to 300 mg of oxalate (0 to 3 3 mmoles) per day Since the weight of the phosphate and oxalate formula are almost equal while the amount of oxalate in the diet is almost 5% the amount of phosphate in the diet a starting dose could be approximately 0 6 to around 2 grams per meal 3 meals per day Therefore the effective amount of PEG-D or PEi D is about 06 to about 2 grams per meal For the formulations that administer the polymers of PEG D or the PEi D polymers of this invention are suitable oral suitable formulations including but not limited to dosage forms such as tablets caplets capsules gel capsules dry powders granulated dry mixtures and other solid and liquid formulations such as suspensions liquid solutions and mixtures with commercially available juice drinks at breakfast and fruit drinks Commonly, pharmaceutically acceptable vehicles are present in the formulation. Therefore, one or more of the following articles are present excipients, binders such as starch, polyvinyl pyrrolidone ( PVP) and pregelatinized starch, lubricants such as magnesium stearate, calcium stearate and stearic acid, and other inert ingredients, including sabopzantes, preservatives, buffer solutions, anti-cake-forming agents, opacifiers, sugars such as sucrose and synthetic endulcoraptes, edible oils such as mineral oils and colorants, may be present in the formulation with PEG-D. Any edible formulation commonly employed in foods, beverages or drug substances may be employed as a formulation in a conventional manner. The final formulations are prepared by the methods known in the field It was also determined that in order to avoid the absorption of phosphate or oxalate from the gastrointestinal tract and minimize the adverse gastrointestinal side effects, the PEG-D polymer or PEi-D polymer as a complexing agent should be greater than about 5000 Daltons and preferably greater than about 10,000 Daltons. However, the polymers of extremely high molecular weights can no longer be soluble in water. water [See Finch CA Chemical modification and some cross-linking reactions of water-soluble polymers, "Chemistrv and Technology of Water-Soluble Polvmers, Finch, CA, ed, Plenum, New York, NY, 1983, pp. 81-111] The molecular weight scale on which these changes occur depends on the polymer of specific PEG or PEi-D that are being considered, but the loss of solubility in water generally occurs above 750,000 Daltons The loss of water solubility makes the PEG or PEi-D polymer less pleasant for patients and less effective for joining phosphate or oxalate The present invention represents a significant improvement over the other known or available agents for removal of phosphate or oxalate from the gastrointestinal tract due to the water solubility of the PEG or PEi-D polymers of the invention, their nature polymer and the lack of the need for a metal ion designed to precipitate phosphate or oxalate Many water-soluble polymers are known and polymers of higher molecular weight use They are less soluble in water than lower molecular weight polymers of the same composition [See Thomson, RA, "Methods of poiymezation for preparation of water-soluble polymers", in Chemistry and Technolov of Water-Soluble Polvmers Finch, CA, ed. , Plenum, New York New York, 1983, pp. 31-70, and Fuchs, OR "Solvents and non-solvents for polymers", Polvmer Handbook. 3rd Edition, Brandrup J And Immergut, E H eds, Wiley, New York, New York, 1989 p. VII / 379 - Vll / 402] The polymers in water of this invention are amine derivatives of polyethylene glycols (PEG-D). These polymers can be prepared by polymethylating an epihalohydrin followed by the depolytization of the resulting polyepihalohydrin to provide the polymer derived from polyetihalohydrin (PEi-D). conditions for the preparation of this PEi-D polymer are provided later) Industrial methods for producing polyethanohydrocarbons also produce short polymer chain lengths with the average molecular weight scale below about 3,000 or molecular weight scales greater than 1. 000 [See EJ Vandenberg J Polym Sci 47., 486-489 (1960), Vandenberg EJ Elastomers, Synthetic (Polyethers) ', Kirk-Othmer Encvclopedia of Chemical Technoloav. Third Edition Volume 8 Kroschwitz, J, ed Wiley, New York, New York 1979, pp 568-582, and Owens, K, Kyl ngstad, VL "Elastomers Synthetic (Polyethers) ', Kirk-Othmer Encvclopedia of Chemical Technology, Fourth Edition Volume 8 Kroschwitz J, ed. Wiley New York, NY, 1993, p.1079-1093] Therefore, this invention also provides the process for producing polyepihalohydrin amine-derived polymers (PEi-D) in the range of 5000 to 750000 Daltops. PEi-D polymers are particularly suitable for use in the invention of the dietary phosphate or oxalate portion from the gastrointestinal tract This invention pertains to water-soluble PEi-D polymers that are capable of complexing phosphate or oxalate and its use to decrease the absorption of dietary phosphate or oxalate respectively from the gastrointestinal tract Such polymers of PEi-D can be described based on the structure of the base of the polymer the substituents attached to the structure of the base, the functional groups that improve the solubility of the water and the functional groups that allow the complexation of phosphate or oxalate The PEi-D polymers of water-soluble complex formation of the present invention comprise polymers having a base structure which provides water solubility and the ability to complex phosphate or oxalate or which leaves the chains Laterals that allow water solubility and functionalization carry out the complexation of phosphate or oxalate and that preferably have an average molecular weight of from about 5000 to about 750,000 Daltons and more preferably from about 10,000 to about 80,000 Daltons The solubility of water of PEi-D polymers of this invention is defined as the ability of the polymer to form a homogeneous mixture of an effective amount of the polymer with water. Preferably the water solubility of the PEi-D polymers of the present invention could involve at least 001 grams (g) of the polymer were dissolved in 1000 milliliters (mL) of water and more preferably at least 1 g of the polymer could be dissolved in 1000 L of water The decrease in phosphate or oxalate from the gastrointestinal tract indicates that the percentage of dietary phosphate or oxalate removed of the gastrointestinal tract removed from the The gastrointestinal tract by absorption in the body is lower when the polymers of PEi-D of this invention are used, than it is when the polymers are not used. This decrease can be determined by comparing the percentage of dietary phosphate or oxalate in the faeces of a animal while the animal ingests the PEi-D polymer with the same percentage when the animal does not ingest the polymer or any other complexing agent with phosphate or oxalate The appropriate consideration of the changes in phosphate or oxalate absorption during growth can be achieved by comparative studies to control animals In addition to corroborating the data for decreased absorption of gastrointestinal phosphate or oxalate from the animal can be obtained by comparing the excretion of phosphate or urinary oxalate as a percentage of the dietary phosphate or oxalate before and after during an oral analysis of the polymer that takes a little more than a few weeks since the excretion of urinary phosphate or oxalate will decrease for the amount of phosphate or oxalate absorbed not enough to maintain phosphate or oxalate homeostasis with normal urinary phosphate or oxalate excretion. An additional corroboration of the decrease in gastrointestinal absorption of phosphate or Oxalate can be obtained by measuring the serum levels of the species before and during administration of the polymer. Examples of polymers included in this invention are water-soluble polymers having a polyethylene glycol base structure depilated with Functional groups (PEG-D) which improve the solubility of water and the ability to form phosphate or oxalate complexes Some of these polymers may require side chains with functional groups that allow water solubility or complexation of the phosphate or oxalate The present invention includes both of these groups of polymers depvatized Examples of side chains that could improve the solubility of water, the ability to form complexes with phosphate or oxalate or include the connection to the polymer base structure, either directly or through C2-C6 alkyl or alkyl groups of C2-C6 aplo, said functional groups such as hydroxyl groups, sulfonates, phosphonates, nitro groups, amine groups, phosphine groups, carbonyl groups, thiol groups, halides and combinations of these groups These examples of polymer side chains are given as examples only and are not intended to limit the side chains or functional groups of the polymers of this In general, it is preferred that the polymers of this invention have a formula weight as small as possible for the polymer monomer unit in order to decrease the dose for the animal. A technique for preparing a glycol base structure Polyethylene (PEG) is the polymerization of an epihalohydrin, such as epichlorohydpna in the presence of a Lewis acid of moderate strength in a solvent that does not act as a chain terminator. Dichloroethane is an example of said solvent, while alcohols or solvents that contain water would not be Preferred These techniques are generally known in the art see for example, U.S. Patent No. 2,871,219, or EJ Vandenberg, J Polymer Sci 47, 486-489 (1960) This particular technique has the advantage of preparing the glycol base structure of polyethylene with a funciopalized side chain (ie, CH2CI) of the base structure that allows easy substitution of other functionalities as will be described below. Another monomer that can be used in similar reactions to create a glycol base structure of Polyethylene with functionalized side chains is 3,4-d-chloro-1-2-butane oxirane. Other methods for preparing a polyethylene glycol base structure with side chains from the base structure to allow for additional functionalization. of the polymer are also included in this invention. These methods include reactions on the previously formed polyethylene glycol to dehydrogenate the binding of the bon-carbon and then introducing the functionality through the double ligation. A preferred starting material for a base structure of polyethylene glycol 11 is an epihalohydrin such as epichlorohydrin or epibromohydrin. As previously explained, it is convenient that the polymers of the present invention are water soluble Some structures of the polymer base contribute to the solubility in water The oxygen atoms in the base structure of polyethylene glycol vanes improve the solubility in water Some polymers can benefit from the operation of side chains for promote water solubility Functionalization of the structure of the polymer base to improve water solubility can be achieved by placing groups that allow the hydrogen bonding to water or ionic dissociation in water. These groups include hydroxyl groups, amine groups, sulfonate groups. , phosphonate groups, carbonyl groups, carbamate groups, nitro groups and carboxylic acid groups These examples are intended only as examples of functional groups which can improve water solubility and are not intended to limit the functional groups of the invention. The inclusion of these groups as Functional groups of the polymers can be made by having the groups in the monomer when the polymer is prepared or by a separate reaction to introduce the group to a polymer. The first technique is demonstrated by the preparation of polyvinyl sulfonic acid and polyacrylic acid. This technique is well known in the matter of polymerization The second technique involves the introduction into the polymer of the desired functionality based on the transformation of the preexisting functionality of the polymer. Such transformations of functional groups are known in the field of organic chemistry. For example Comprehensive Oraanic Transfornations A Guide to Functional Group Preparations, by Richard C Larock presents many preparative routes for the introduction of several functional groups. This reference includes tables that list the desired functionality of the present functionality and the reaction sequences that have been reported to achieve the transformation. Other sources of Preparative techniques include Advanced Organic Chemistry Reactions. Mechanisms, and Structure. Fourth Edition, by Jerry March Nitration Methods and Mechapisms by George A Olah, Ripudaman Malhotra and Subhash C Narang, and Advanced Qrqanic Chemistrv by Francis A Carey and Richard J Sundberg, Plenum Press, NY, 1990 Additionally, the polymers of the present invention have the ability to complex with phosphate or oxalate, as discussed above. To do so, it is preferred that the polymer base structure contain a portion or that it be functionalized with a portion that allows the formation of complexes with phosphate or oxalate. cation at physiological pH (approximately pH 65 to 75) to which it is exposed will generally facilitate complexing with phosphate or oxalate. Amines and phosphines are examples of such portions that can be cationic at physiological pH. To form complexes with phosphate or oxalate, amines should be quaternary amines or be able to be converted to quaternary amines under physiological conditions. Similarly, the phosphines will be quaternary phosphines or they will be able to easily convert to quaternary phosphines under physiological conditions in order to be cathodic. Therefore the amines or polyamines can be primary secondary, tertiary and quaternary The most preferred functionalities include those selected from the group consists of ammonia ethyleneamines amines of alkanol and amines of C1-C10 alkyl The reactions Preparations for introducing these groups can be found in the same references mentioned above for the functional groups designed to improve water solubility. Therefore, the polymers of the invention (PEG-D) can be prepared in one or two steps. for formation of phosphate complexes or water-soluble oxalate complex formation polymers can be prepared in one step when the monomer contains appropriate functionality in order to allow polymerization which produces an appropriate base structure and simultaneously produces side chains with functionality that can complex with phosphate or oxalate Whether in the base structure the side chains or both could result in water solubility Two Steps In the two-step process the first step involves the preparation of a base structure with appropriate leaving groups. These leaving groups are replaced in the second step to introduce the desired functionality required to improve the water solubility in order to improve the capacity of complex formation or both. aspect of the present invention is the use of these polymers of PEG D or PEi D as non-systemic agents in the prevention of absorption of dietary phosphate or oxalate in the gastrointestinal tract For this application it was discovered that the solubility in water and size play important roles How I know described earlier the solubility in water improves the mixing of the complexing agent with the target compound that leads to the formation of more effective complexes In addition the solubility in water makes the agent more pleasant thus increasing the compliance of the patient The size of the molecule in this type of application is important since molecules less than about 1,500 Daltons can be absorbed from the gastrointestinal tract in the bloodstream which is not convenient for the present invention Molecules between 1,500 and about 5000 Daltons are not absorbed from the gastrointestinal tract but can cause an osmotic effect that draws water into the intestine and causes diarrhea and possible dehydration Water solubility generally decreases with increasing polymer size Because of this there may be a higher molecular weight limit of about 750000 Daltons for polymers of this invention in addition to decreased r about the molecular weight described above For some polymers the base structures of the appropriate length can be achieved using means known in the art. For example, polyvinylpyridinone of appropriate molecular weight is obtained by polynucleotide vinylpyrrolidone followed by separation of the resulting mixture of weights Molecules through size exclusion membranes or size exclusion preparative chromatography Other polymers can be prepared on the correct molecular weight scale by the judicious choice of molar ratio of monomer to moles of catalyst and the starting reaction mixture However, some polymers are difficult to prepare on the preferred weight scale. These polymers usually require such vigorous catalysts to begin polymerization, that only very short polymers are formed before the side reactions stop the polymerization When the catalysts of these polymerizations are partially inactivated in an attempt to allow better control of degree of polymerization, the reaction proceeds to extremely large molecular weights and the ability to control the degree of polymerization. These subjects are well known in the field and are treated in Allcock, HR and Lampe FW, Contemporarv Polvmer Chemistrv. Second edition. Prentice Hall Englewood Cliffs, New Jersey, 1990, pages 21-333, and in Young, R J and Loveil, P A Introduction to Polvmers. Second Edition, Chapman and Hall, New York 1991, pages 15-133 Separation techniques, such as those described for polyvinylpyrrolidone, can be successful in processing polymers with high degrees of polymerization and isolating those polymers with lower molecular weights. invention, is that the polyepiclorohidpna polymers (PEi-D polymers) having a molecular weight of 5,000 Daltons and greater, more preferably at least 12,000 Daltons even more preferably at least 15,000 Daltons The polymers of this invention may have any molecular weight above these minimums but preferably they are less than 750,000 Daltons, more preferably less than 500,000 Daltons, still more preferably less than 300,000 Daltons and especially more preferably less than 80,000 Daltons. Generally polyepiclorohidpna polymers have not been prepared on the preferred molecular weight scale. Many polyether polyhydrobenic polymers reported in the prior art they had a very low molecular weight, usually below 3,000 Daltons [See T Aída et al., Macromolecules 21, 1195-1202 (1988), A Le Borgne et al., Makromol Chem, Macromoi. Symp 73, 37-46 (1993), and R Nomura et al., J Polym Chem 26., 627-636 (1988)] These polymers are usually formed with catalysts that were very strong, such as aluminum alkyl or boron compounds When the oxygen-containing compounds were added to the aluminum catalysts to partially activate them, polyepiclorohidpna resulted that had molecular weights greater than 1, 000,000 Daltons [See U.S. Patent No. 2,871,219, EJ Vandenberg, J Polymer Sci 47, 486-489 (1960), and J Wu and others Polym J 22, 326-330 (1990)] It was discovered in the present invention that the appropriate weight scale of pohepichlorohydpna could be made using catalysis by t-heptyloxionium hexafluorophosphate or by 1,2-ethylene d (tr? fluoromethanesulfonate), ie "1,2-Ethyl ditpflate". The tetyloxionium hexafluorophosphate is has reported as a catalyst capable of polimepzar epichlorohydpna by adding epichlorohydpna groups to each end of a central ethylene glycol for form molecular weights between 900 and 1000 Daltons [See Okamoto Y "Cationic png-opening polymepzation of epichlorohydrin in the presence of ethylene glycol Rinq-openinq Polimepzation Kinetics Mechanisms and Svnthesis McGrath JE ed ACS Washington DC 1985 286361-372] The present invention is refers to the preparation of polyepiclorohidpna without the presence of ethylene glycol The present invention has produced poliepiclorohidpna of appropriate molecular weight through the control of polymerization termination reactions This control was obtained by the careful distillation of all reagents and solvents to exclude water control careful of the temperature during the exothermic reaction and judicious control of the ratio of the catalyst molecules to epichlorohydrin molecules at the beginning of the reaction The continuous addition of epichlorohydrin to the reaction mixture after establishing a number of growth polymers that have been initiated also allowed the co Optimal control over the molecular weight of the polymer Another method for preparing the desired molecular weight of polyepichlorohydpna is the use of ethyl ditpflate as a catalyst. A third method for producing polyepichlorohydpine with molecules on the appropriate weight scale is the use of fluobopco acid. as a catalyst with the appropriate temperature control and addition rates When it is necessary to improve the water solubility the ability of complex formation or both of the polymer placement on the base structure of various functionalities such as ammocarboxylate amines, crown ethers, azamacrocycles or carboxylates can be achieved in a second step. The choice of functionality is made depending on the desired activity of the resulting water-soluble complexing polymer. Preferably, convenient functional groups will complex phosphate or oxalate in one mole of phosphate or oxalate to one mole of base of complexation site of monomers and will allow the necessary amounts of the polymer for the individual doses, such as 1 to 10 grams, which are soluble in small amounts of water, such as 2834 to 22672 grams Ideally, a functional group could perform both tasks, but it may be necessary to place two or more different groups on the structure of the polymer base The placement of the desired group or groups of complex formation on a structure of the polyethylene glycol base is carried out by the appropriate reactions depending on the In the preferred embodiment of the invention wherein the polymer base structure is prepared from the epichlorohydrin the functionalization of the polyepichlorohydpna was carried out by reacting it under nucleophilic conditions with an appropriate amine to provide the required reactivity for the desired use of the water soluble chelating polymer. For example if the situation only requires phosphate binding in an acidic environment then the acid can protonate a amine to an ammonium which, being positively charged, will bind to an anion such as phosphate or oxalate. Therefore, the use of a primary or secondary amine (such as ethylenediamine diethylene glycine as the free material or with the blocked primary amines to force substitution in the secondary nitrogen, or higher analogues of ethyleneamm), with one nitrogen displacing the heat while the other nitrogen remains free to protonate and bind to the anion. Although the substitution of ammonia for the chlorine atom can provide an amine capable of protonation. On the other hand, it is necessary to bind the phosphate even in alkaline conditions (such as the case of the binding of phosphate in the gastrointestinal tract of a patient who is being treated with Tagamet ™ so that there is no acidity in the stomach), an amine Tertiary, such as t-methylamine, can replace the chlorine atom. This could result in a quaternary ammonium compound which is charged positively regardless of the pH Therefore, for example, a polymer of the formula wherein each R can independently represent hydrogen an unsubstituted C6-C6 alkyl group which may be branched or branched unbranched an C6-C6 alkyl group which can be unbranched, branched or cyclic, a C6-C or C? not replaced a group of C6-C aplo? its substituted or 1 or 2 R groups may be absent (v gr where only one of the R groups may be absent) as is the case when the nitrogen described only has three substituents (including the connection to the base structure of the poly number) instead of four substituents, which may be an example of the polymers of this invention. For example, when ethylenediamine is substituted on polyepiciorohydpna the formula could have a group R as hydrogen a group R as an aminoethyl group and a absent R group In another example, the tmethyl amine is replaced by polyepichlorohyd pna resulting in the above formula in which each of the three R groups can be a methyl group. In a further example the hexadecylamine is substituted in polyepichlorohydrin giving as a summary A group R that is a hexadecyl group is a group R being a hydrogen and a group R is absent When high selectivity or high constants are needed For the complex, the polyepichlorohydpna or other water-soluble polymer can be replaced with a macrocyclic compound with oxygen nitrogen sulfur or a combination of these as the heteroatoms in the macrocycle such as ethers of azocoron ethers ethers ethers of thiocoronamiento ciclodextp nas op orfi rmas [See for example RM Izatt and others Chem Rev 91. 1721 2085 (1991) and S Tamagaki and others Supramol Chem 4 159 164 (1994)] In cases where macrocyclic complex formation groups are substituted on the polymer another functionality could also be required to ensure solubility in water PEi polymers are depolytized to form the corresponding PEi-D polymers in the manner treated above When the amine group is desired as the fuptionalized group in the derivative the PEi can be reacted in the pure amine solvent Usually a minimum of a molar excess of four times preferably a molar excess of 12 to 16 is used times of amine to the chloromethyl group in the PEi An exception to this molar requirement was tmethylamine where as little as 05 moles of the amine was required to one mole of PEi in a 20% aqueous solution. The water was usually kept outside the system. reaction during this step because the water contributes to the hydrolysis of the chloromethyl groups in PEi The temperature scale for the reaction is approximate from 25 to about 120 ° C The remainder of the reaction was operated as described above and in the examples The conversion of chlorine to the chloromethyl group in polyepichlorohydpna to the amine derivative is from about 10 to about 80% The invention will be further clarified by a consideration of the following examples which are intended to be illustrative only of the present invention. General Experimental Procedures A Method for determining the amount of amine added to the polyepichlorohydride (PEi) The amount of functionalization of etiiendiamine (EDA) in a polyepichlorohydpna polymer was determined by a copper titration method. The PEi / EDA solution was titrated with a solution of copper chloride in the presence of a Murexide ™ indicator. The copper was chelated by the EDA to saturation at which point the excess copper complexed to the indicator and this end point was observed using a colopmetpco detector. The solutions required for the titrant Memo METTLER DL40GP 1 A solution of copper chloride 001M prepared by adding 1 705 g (001 mole) of cupric chloride. { CuCl2 «2H2} [Fisher] (FW17048) to a one liter volumetric flask and diluting to the mark with deionized water 2 A pH buffer solution of sodium acetate 0002M prepared by adding 0 272 g (0002 mole) of sodium acetate tphidrate. { CH3COONa «3H20} [Fisher] (FW13608) to a one liter volumetric flask and diluting to the mark with water 3 An indicator solution of 0 1% Murexide ™ prepared by adding 5 g (00176 moles) of ammonium purpurate acid [from Fisher] ] (FW284 19) to a 500 mL volumetric flask and diluting to the mark with water Specialized 125 L disposable polyethylene sample agitators (made to fit a sample changer) were tared to a balance of 163 METTLER® AE and charged with an aqueous solution of PEi / EDA (an amount estimated for supply ~ 8 mg of PEi / EDA) The weight of this sample was automatically recorded in method 364 of a METTLER55 DL 40GP Memo Titrator To this solution of PEi / EDA was added 80 mL of deionized water 40 mL of an aqueous solution 2 mMolar of sodium acetate and 05 L of an aqueous solution of 0 1% of ammonium purpurate acid (Murexide ™ indicator) The sample solutions were placed in the sample changer and were titrated with a copper chloride solution 001 M The endpoint was observed using a METTLER * DP550 Phototrode colopmetpco detector and was introduced into the Titration Memo The amount of functionalization in the poly-epipolymer could be calculated based on the number of moles of copper chelated by ED A An example of this titration method can be seen in the following Table I From the data in Table I above, it is evident that the more ethylenediamma (EDA) is used as a reagent with the poiiepi polymer (PEi) and the higher the reaction temperature, the greater the amount of EDA added to the structure of the polymer base Based on observations in numerous experiments in which the polyepi polymers were functionalized with several amines, the greater the number of amines bound to the PE polymer, the greater the solubility of the water. The solutions of > 50% by weight of PEi / EDA have been achieved at ambient temperatures B The procedure for molecular weight determination involves gel permeation chromatography For the determination of polyepiclorohidpna before the depolytization is carried out a column PL- is used Mixed E gel with tetrahydrofuran used as the solvent for the sample and as the eluent The calibration was provided by comparison to the commercial polyethylene glycol polyethylene normal standards. The flow rates were controlled at 1 ml / min at a temperature of 40 ° C column Samples were dissolved in tetrahydrofuran at a concentration of 0.25 weight percent and filtered to remove any particles (which may include some high molecular weight polymer). A cycle injector is used to inject 150 microliters of solution into the column. The resulting chromatograms are used to determine Mn, Mp, Mz and z +? by mathematical calculation with the software in the computer's controller. All supported molecular weights will represent measurements of Mp. The molecular weight measurement of the derivatized polyepichlorohydrin polymers was carried out with a TSKgel 2000PW + 3000PW + 5000PW column using 0.1M NaCl, 0.1M EDA in methanol / water at 1 to 1 of 1 ml / min. and at a column temperature of 40 ° C. The injection volume was 100 microliters. The samples were dissolved in water at a concentration of 1% and filtered before injection. The values of Mp. The invention will be further clarified by the consideration of the following examples, which are intended to be illustrative only of the present invention. EXAMPLES Starting Materials Example A: Preparation of polyepiclorohydrin (PEi) Using Triethyloxionium Hexafluorophosphate In a dry atmosphere, 0.1257 g of triethyloxionium hexafluorophosphate was dissolved in 9.4438 g of dry methylene chloride. The distilled epichlorohydrin (78.4 g) was placed in a container rinsed with dry nitrogen and immersed in a water bath. constant temperature at 40 ° C The solution of t-heptyloxionium hexafluorophosphate was added to the epichlorohydrin with stirring and was allowed to react for twenty-four hours. The temperature rose to 70 ° C when the reaction mixture became more viscous. The resulting material was rinsed with ethanol three times Forty-eight grams of material were obtained Gel permeation chromatography revealed a molecular weight scale of 3, 000 to 400,000 Daitons, with an average molecular weight (Mp) of 100,000 and 90% of the polymer having molecular weights between 5,000 and 100,000 Daltons Example B Preparation of Polyepiclorohidpna (PEi) Using Fluobopco Acid In an atmosphere, 450 mL of methylene chloride , 1 0 of 48% aqueous fluoroacid acid and 10 mL of 54% fluocopoc acid in diethyl ether were heated to 40 ° C. This composition was slowly added with 850 mL of epichlorohydrin and heated to reflux until the reaction was complete. The reaction was evaporated with a rotary evaporator under reduced pressure and temperatures up to 100 ° C until no more solvent could be removed. The molecular weight of the polymer by gel permeation chromatography was 3500 Daltons (M ") with more than 40% of material above 14000 Daltons Final Products Example 1 Preparation of Polyepiclorohidpna / Tpmethylamine (PEi / TMA) A 2 liter stainless steel PARR pressure reactor was charged with 185 g (2 moles) of polyethylene glycol polymer of molecular weight above 5,000 Daltons (PF 9253 per unit of repeating monomer) To this polyether polyhydroxyl polymer were added 2465 g (1 mol) of 24% by weight of the tmethylamine solution (PF 59 11) the reactor was sealed and placed in a PARR heater / agitator unit and pressurized to 52 kg / cm2 (Pa) with nitrogen. reaction vessel was heated to 115 ° C with constant stirring. The reactor was maintained at 115 ° C and 52 kg / cm2 (Pa) for sixteen hours The reactor was cooled, ventilated at atmospheric pressure and opened. The reaction solution was filtered through a filter paper No. 1 on a 90 cm Buchner filter under vacuum then transferred to a round bottom flask. 500 mL This solution is rotoevaporated at 70 ° C and 2032 cm vacuum pressure water at 80 mL volume This reaction product was transferred to a Spectra / Por ™ membrane bag [molecular weight cutoff 14000] and dialyzed into 254 cm of deionized water for sixteen hours to remove any small molecular weight species sm react The molecular weight was approximately 18000 Daltons (Mp) Example 2 Preparation of Polyepiciorohydrin / Tri etiiamma / Ammonium hydroxide (PEi / TMA / NH "OH) A 2 liter stainless steel PARR pressure reactor was charged with 236 g (025 moles) of polyepichlorohydpna (PF 9253 per unit of repeating monomer) To this polymer of polyepiclorohidpna was added 250 L of water and 308 g (0125 mole) of 24% by weight of tpmethylamine solution (PF 59 11) The reactor was sealed and placed in the PARR heater / agitator unit and heated to 105 ° C. C with constant stirring The reactor was maintained at 105 ° C and 32 kg / cm2 for sixteen hours. The reactor was cooled, vented at atmospheric pressure and charged with 450 g (77 moles) of 29% by weight hydroxide solution. ammonium (PF 17) The reactor was resealed and placed in a heater / stirrer unit and reheated to 105 ° C The reactor was maintained at 150 ° C and 56 kg / cm2 for sixteen hours The reactor was then cooled, ventilated and opened. The reaction solution was filtered through a filter paper No. 1 on a 90 cm Buchner filter under vacuum then transferred to a 500 mL round bottom flask. This solution was rotoevaporated at 70 ° C. C and 5842 cm of vacuum pressure of water at a volume of 80 mL. This reaction product was transferred to a Spectra / Por ™ membrane bag [cut-off molecular weight 3,500] and dialed into 254 cm of deionized water for eighteen hours. This solution was then lyophilized to a light tan hygroscopic solid Example 3 Preparation of Polyepiclorohidpna / Dietilentpamine (PEi / DETA) A 500 mL three-neck round bottom flask was fitted with a reflux condenser, a thermometer to which the THERMOWATCH l2R temperature controller was attached and an addition funnel The flask was charged with 4127 g of dietilentpamma (PF 1032) and then heated to 120 ° C. An addition funnel was charged with 377 g (O 41 moles) of polyepiciorohydpna with a molecular weight of more than 5,000 (weight of the monomer 9253 g). The polyepichlorohydpna was added to the diethylene glycol to a rate of approximately 025 mL per minute followed by continuous heating of the reaction mixture for an additional 60 minutes and cooling to 45 ° C The sodium hydroxide solution (328 g, 041 mol) of the 50% solution ai and 150 mL of Water was mixed with the reaction mixture and stirred for 45 minutes, filtered with filter paper to remove a white precipitate and dialyzed with a Spectra / Por ™ membrane with 3,500 Daltons molecular weight cut-off. The solutions were then lyophilized to produce bfanco powder materials, having an average molecular weight of about 18,000 Daltons (Mp) Example 4 Preparation of Polyepiclorohidpna / Ethylenediamine (PEi / EDA) A 2000 L three-necked round bottom flask I adapt with a stir bar, a reflux condenser, a 10 mL addition funnel and a thermometer to which was attached a temperature controller THERMOWATCH lzR The flask was charged with 360 g (6 moles) of ethylenediamine (EDA), (PF 601) The funnel of addition was charged with 231 g (25 moles) of polyepiclorohidpna polymer (PF 92 53 per unit of repeating monomer) with a molecular weight above 5,000 Daltons and about 40% of the molecules above 12,000 Daltons. reaction containing EDA was heated to reflux (100 ° C) with constant stirring at which point the polyepichlorohydride polymer was added dropwise to ethylenediamine at a rate of 45 mL per minute. The reaction was continued for 16 hours after the addition of all the polyether-polyhydrin polymer. The reaction was then transferred to a round bottom flask and rotoevaporated at 75 ° C and 5842 cm vacuum water pressure to remove the unreacted ethylepdiamma. The polyepiclorohydma / EDA solution was transferred to a Spectra / Por ™ membrane bag [ 14000 molecular weight cut] and dialyzed in 254 cm of deionized water for eighteen hours This solution was then freeze-dried to a light tan hygroscopic solid. Gel permeation chromatography revealed an average molecular weight of over 17,000 Daltons (Mp) Example Comparative D Preparation of Polyalylaminobiguanide (PAAG) In a dry beaker 936 g of polyallylamine hydrochloride (0 1 mol purchased from Aldrich with a molecular weight of 50000 to 65000 Daitons) were mixed with 20 mL of 10 M NaOH and sufficient water to allow agitation The liquid was decanted and the ream was washed with water and dried The resin was suspended in 300 L of methanol in a round bottom flask and mixed with 20 12 g of 35-d? met? lp? razol-1-carbox? am? da nitrate (0 1 mole) The mixture was refluxed for 96 hours The ream was then filtered and rinsed with methanol and dried The product has a molecular weight above about 75,000 Daltons Comparative Example E Preparation of Pol? (Al? Lam? Na-N- (2-hydrox? -3-tpmet? Lamon? Or propyl) polyallylamine with a molecular weight of 52,000 to 83,000 Daltons (1 88 g, 002 moles) was placed in a reaction vessel and mixed with 404548 g of 3M NaOH (0121 moles). N, N N -tpmethyl-oxiranomethanamine chloride (200150 g of 652% solution 0086 moles) was added. The reaction mixture it was heated to reflux overnight and dialysed in a hemodialysis bag of molecular weight cut-off of 3500 against deionized water. The resulting solution was lyophilized resulting in 1 8 g of tan solid color. The solid is and has a molecular weight of more than 75,000 Daltons. Comparative Example F Preparation of Poly (Allyl-N Nd? methalamino) -N- (2-hydroxy? -3-tr? methalamon? or propyl chloride) ) Polyallylamine with molecular weight of 52,000 to 83,000 Daltons (0 9356 g 001 moles) was dissolved in 5 g of acetonitoplo and reacted with 36 L of 3M NaOH (00108 moles) to obtain a pH of 74 Methyl iodide (284 g, 0 02 mol) was added and the reaction mixture was heated to reflux. During reflux, an additional 08 mL of 3M NaOH (00024 mol) was added to raise the pH to 7 9. N, N-N-tpmethyl-oxiranomethanamine chloride (5 77 g of 652% solution, 0 025 mol) was added and reflux heating was continued. After 24 hours, the reaction mixture was placed in a cutting hemodialysis bag. of 3,500 Daltons and dialyzed overnight in deionized water The resulting solution was 11 of 11 izo resulting in 56 g (58% yield) of a tan powder The compound is which has a molecular weight of more than 75,000 Daltons Biological Experiments Example I Prevention of Gastrointestinal Phosphate Absorption by the Use of Polyepiclorohidpna / Ethylenediamine The rat feed containing 0 65% in grams of phosphorus from the mixed grains was mixed with polyepiclorohidrma / ethilendiamma prepared by the Process of Example 4 The food was prepared by mixing enough polyepichlorohydpna / ethylenediamine with the feed of rats to have 3 moles of binding sites per mole of phosphate in the feed 1 mole of binding sites per mole of phosphate in the feed 05 moles of sites of binding per mole of phosphate in the feed and 0 mole of binding sites per mole of phosphate in the feed (the control group) Six rats were each fed with this diet for one week During these experiments the urinary phosphate at the end of the average week 182 mg / day for controls 8 7 mg / day in group 0 5X 86 mg / day in group 1X 1 9 mg / day in group 3X Lower urinary phosphate levels indicate that rats reacted to the lack of obtaining enough dietary phosphate while preserving the phosphate by limiting renal excretion The total phosphate balance (dietary intake of urine output in faeces) at the end of the week was 478 mg / day for controls 509 mg / day for group 0 5X 343 g / day for group 1X and 39 5 mg / day for group 3X Comparative Example A Prevention of Gastrointestinal Absorption of Phosphate by the Use of Polyalilamma (RenaStat ™) Polyaiilamma hydrochloride with a molecular weight of 50000 to 65,000 was obtained from Aldrich and used without further purification Rat feed containing 0 6% gm of phosphorus from the mixed grains was mixed with polyallyamine in a ratio of 98.04 grams of powdered rat feed to 1 96 grams of polymer to provide a ratio of an amine binding site for each phosphate present in the feed Two 125 gram rats were fed ad libitum with this diet and compared with rats fed ad libitum with non-altered powder feed for rats Before starting the special diet and after a period of two weeks of stabilization the recoveries Twenty-four hours of stool and urine were obtained from each group of rats and analyzed for phosphorus by inductively coupled plasma spectroscopy. Since the control rats decreased their growth rate during two weeks the percentage of dietary phosphorus found in the beams it increased from 65% to 72% (increase of 7%) while rats with polyallylamide hydrochloride showed an increase of 58% to 75% (increase of 17%) of dietary phosphorus being poorly absorbed which is 26 times the Increased phosphate loss found in the control rats During the same time the control rats showed an increase in the urinary phosphorus from 6% to 16% of dietary intake while rats with polyallylamine hydrochloride decreased their output of urinary phosphate from 6% to 2% of dietary phosphate intake at the end of the study This indicates that rats with po alilamma retained phosphorus urinary compared to the control rats indicating that they could not absorb the appropriate phosphate from their diet Example II and Comparative Example A Prevention of Gastrointestinal Phosphate Absorption with Polyalylammobiguanide Two 125 g Sprague Dawley rats were given oral Nulytely ™ to remove all the material from their gastrointestinal tracts. After this preparation one of the rats was given a milk fattening feed designed to deliver 0324 millimoles (mmol) of phosphate The other rat was fed with priming with the same amount of milk mixed with 00322 g of the polyalylaminobiguamda prepared in Example 5 After 1 hour both rats were again given Nulytely ™ to remove and recover all of the unabsorbed feed from the gastrointestinal tract Phosphate was measured in stool collected by inductively coupled plasma spectroscopy Phosphate that was not absorbed by the rat receiving the polyalylammobiguanide was 66% of the phosphate that was not absorbed by the control rat Example III and Comparative Example B Phosphate Complexation by Poi Chloride (al? Lam? Na-N- (2-h? Drox? -3-tr? Met? Lamon? Or propyl)) The poly (allylamine-N- (2-hydroxyl-3-methylmethane) propyl chloride) prepared by the procedure of Example 6, was dissolved in water 072 g in 10 mL form a solution of 0345M In each of the four tubes 0454 mL of this solution (0 19 mmol of units of monomer) were mixed with 10 mL of NaH2PO 00207 M and appropriate amounts of HCl and NaOH to form solutions of pH 3 pH 45 pH 6 and pH 75 The tubes with the same pH were also prepared with 10 mL of NaH2PO < 00207 M and 050 ml of CaC03 1 5M (0749 mmoles) The control tubes were also prepared with the sodium phosphate solution and the adjustment All the tubes were diluted to 12 mL with water The tubes were shaken for one hour The solutions were placed separately in 30 Centpcon ™ molecular weight cutting tubes and centrifuged for 30 minutes The recovered filtrate was analyzed for phosphorus by inductively coupled plasma spectroscopy The polymer removed 58% phosphorus at pH 3.59% phosphorus at pH 45, 56% phosphorus at pH 6, and 44% phosphorus at pH 75. Calcium carbonate removed 16% of the phosphorus at pH 3, 13% phosphorus at pH 45, 9% phosphorus at pH 6, and 7% phosphorus pH 75 Control tubes showed 07% phosphorus removed at pH 3.1.1% of phosphorus removed at 07 % of the phosphorus removed at pH 6 and 06% of the phosphorus removed at pH 75. Therefore, the polychloride (al? lam? na-N- (2-h? drox? -3-tr? met? lamon? or propyl)) was effective in complexing the phosphate Example iV and Comparative Example C Phosphate complexing by Pol? chloride (al? iN, Nd? Met? Iam? No-N- (2-h? Drox? -3-tr? Met? No propyl)) Pol? Chloride (al? N, Nd? Met? Lam? No-N) - (2-hydroxy-3-trimethylammonium propyl)) prepared as in Example 7, was dissolved in water as 072 g in 10 L to form a solution of 0263 M In each of the four tubes, 067 mL of this solution (0 18 mmoles of monomer units) was mixed with 10 mL of NaH2P04 00207 M and appropriate amounts of HCl and NaOH to form solutions of pH 3, pH 45, pH 6 and pH 75 The tubes with the same pH were also prepared with 10 mL of NaH2PO 00207 M and Or 50 mL of 1 5 M CaC03 (0749 mmol) The control tubes were also prepared with the sodium phosphate solution and the pH was adjusted All the tubes were diluted to 12 mL with water The tubes were shaken for one hour The solutions then they were placed separately in Centpcon ™ 30 molecular weight cutting tubes and centrifuged for 30 minutes The recovered filtrate was analyzed for phosphorus by inductively coupled plasma spectroscopy The polymer removed 49% phosphorus at pH 3 53% phosphorus at pH 45 48% phosphorus at pH 6 and 39% phosphorus at pH 75 Calcium carbonate removed 16% phosphorus at pH 3 13% phosphorus pH 45 9% phosphorus at pH 6 and 7% phosphorus at pH 75 The control tubes showed 07% of the phosphorus removed at pH 3 1 1% of the phosphorus removed at pH 45 04% of the phosphorus removed at pH 6 and 06% of the phosphorus removed at pH 75 Therefore the pof i chloride ( I il - NN d? meí? lammo-N (2-h? drox? -3-tr? met? lamon? o)) was effective in complexing the phosph ato Example V Oxalate complexation by Poliepiciorohidpna / ESA and Polyepiclorohidpna / DETA A solution was prepared 0025M of ammonium oxalate. Polyepichlorohydrin was prepared using the procedure of Example A having a molecular weight of about 45,000 Daltons EDA derivatives were formed (Example 4 above) and DETA (Example 3 above) The solutions of these two derivatives were used to place 0001 moles of binding sites on separate molecular weight cut-off filters (Centpcont concentrators after they added 0001 moles of oxalate to each concentrator and a control containing only water. The solutions were mixed together for one hour and then centrifuged. The filtrates were analyzed for oxalate by GC-MS and compared to the concentrator that only had oxalate. Both polymers derived of ESA and DETA absorbed approximately 30% of oxalate Example VI Prevention of Gastrointestinal Phosphate Absorption by the Use of Polyepiclorohidpna / Tpmethylamine / Ammonia The rat feed containing 065% gm of phosphorus mixed grains was mixed with polyepiclorohidpna / tpmethylamine / ammonia prepared in Example 2 in a ratio of 9764 grams of powdered rat feed to 236 grams of polymer to provide a ratio of an amine binding site for each phosphate present in the feed Two 125 g rats were fed ad libitum with this diet and were compared with two rats fed ad libitum with unaltered powdered rat feed Before After a period of two weeks of stabilization, separate recoveries were obtained during twenty-four hours of excrement and urine from each group of rats and analyzed for phosphorus by inductively coupled plasma spectroscopy. As the control rats decreased their During the two weeks, the percentage of dietary phosphorus found in the excrement increased from 65% to 72% (increase of 7%) while the epiclorohydrin / tpmethylamine / ammonia rats showed a increase from 65% to 76% (11% increase) of the dietary phosphorus that was not absorbed which is 1 6 times the increased phosphate loss found in the control rats. During the same time the control rats showed an increase in phosphorus urinary from 6% to 16% of the dietary intake while the rats in poliepiclorohidpna / tpmethylamine / ammonia had 7% of the dietary phosphorus in their urine over the normal diet and 10% of the dietary phosphorus in the urine at the end of the study. , the rats in polyepiclorohidpna / tpmethylamine / ammonia retained phosphorus compared to the control rats indicating that they were not able to absorb adequate amounts of the phosphate from their food Example VII Prevention of Gastrointestinal Phosphate Absorption by the Use of Polyepiclorohidpna / Trimetilamma The food of rats containing 065% gm phosphorus of mixed grains was mixed with polyepichlorohydpna / tpmethylamipa prepared in Example 1 in a ratio of 9682 grams of powdered rat feed to 3 18 grams of polymer to provide a ratio of an amine binding site for each phosphate present in the feed Two 125 gram rats were fed ad libitum with this diet and compared with the two rats fed ad libitum with non-altered powdered rat feed Before starting the special diet and after a period of two weeks of stabilization, excrement and urine collections were obtained separately from twenty-four hours from each group of rats and they analyzed for phosphorus by inductively coupled plasma spectroscopy. As the control rats decreased their growth rate during the two weeks, the percentage of dietary phosphorus found in the excrement increased from 65% to 72% (increase of 7%) while rats with poliepiclorohidpna / tpmethylamine showed a decrease of 62% to 59% (decrease of 3%) of the dietary phosphorus that was not absorbed. During the same time the control rats showed an increase in the phosphorus or rinar from 6% to 16%. % (increase of 16%) of dietary consumption while rats with poliepicloroh id pna / tpmethylamine had 6% dietary phosphorus in their urine in the normal diet and 9% of the dietary phosphorus in the urine at the end of the study ( 3% increase) This moderate or indigenous increase in rats with polyepichlorohydpna / tp methylane retained phosphorus compared to control rats. Other modality of the invention will be It is clear to the experts in the art from a consideration of this specification or practice of the invention described herein. It is intended that the specification and examples be considered as illustrative only with the scope and actual spirit of the invention. nished by the following claims

Claims (1)

1. CLAIMS 1 A water-soluble polyether glycol polymer comprising a structure of the structural base of carbon atoms and oxygen atoms wherein at least two consecutive carbon atoms are present between each oxygen atom a portion of the structure of the base of the polymer or a functionalized derivative in the polymer that is cationic at physiological pH and allows complexation with phosphate or oxalate an average molecular weight of about 5000 to about 80000 Daltons and wherein the solubility of the polymer is at least 001 grams of the polymer per 1 000 mL of water 2 The polymer of claim 1 comprising an average molecular weight of from about 10,000 to about 80000 Daltons The polymer of claim 2 comprising an average molecular weight of about 12,000 to about 80000 Daltons 4 The polymer of claim 2 comprising an average molecular weight of about 1 5000 to about 80000 Daltons The polymer of claim 1 wherein the polymer has been depilated with functional groups 6 The polymer of claim 5 wherein the functional groups are directly connected to the polymer base structure or connected by groups alkylene of C C6 or C2-C6 alkyl-C6-C12 alkyl and selected from amine and phosphine or combinations of these groups 7 The polymer of claim 6, wherein the polymer is a polypipelohydrin derivative The polymer of claim 7, wherein the polyepihalohydrin derivative has an average molecular weight of between about 15,000 to 80,000 Daltons The polymer of claim 7, wherein the polyethihalohydrin derivative is a polyepichlorohydrin amine The polymer of claim 9, wherein the derivative is a group of tpmetilamma 11 The polymer of claim 9, wherein the derivative is a group of tetylenetetramine 12 The polymer of claim 9, wherein the derivative is a group of ethylene diamine The polymer of claim 9 wherein the derivative is a group of diethylene glycine 14 The polymer of claim 9, wherein the derivative is a tetraethylene pentamine group. The polymer of claim 9, wherein the derivative is a mixture of two or more amine groups 16 The polymer of claim 1, wherein the solubility of the polymer is 1 to 10 grams of the polymer per 10 L of water 17 A formulation for oral administration comprising a polymer of claim 1 with a pharmaceutically acceptable carrier. The formulation of claim 17 wherein the polymer is a derivative of polyepihalohydpna. A method for the reduction of phosphate or oxalate m alive in a animal comprising administering an effective amount of a formulation of claim 17 The method of claim 19 wherein the formulation is of claim 18 The method of claim 20 wherein the effective amount for the phosphate reduction is about 1 to about 15 grams per meal 22 The method of claim 20 wherein the effective amount for the oxalate reduction is from 06 to about 5 grams per meal 23 The use of a polymer of claim 1 as an agent for the reduction of phosphate or oxalate m alive in an animal A process for preparing the polymer of claim 1 which comprises reacting an epihalohydrin in the presence of a moderate strength Lewis acid in a solvent that does not act as a chain terminator. The process of claim 24 wherein the solvent is dichloromethane 26. A process for preparing the polymer of claim 1, which comprises reacting a 3,4-dichloro-1,2-butane oxirane, in the presence of a Lewis acid of moderate strength, in a solvent that will not act as a terminator chain. 27. The process for preparing the polymer as defined in claim 1, wherein a catalyst is present selected from triethyloxyion hexafluorophosphate, fluoboric acid, triethyl aluminum and 1,2-ethyl di (trifluoromethansuifonate).