MXPA00004329A - Unsubstituted polydiallylamine for treating hypercholesterolemia - Google Patents

Abstract

A method for removing bile salts from a patient that includes administering to the patient a therapeutically effective amount of a non-absorbable polydiallylamine polymers.

Description

METHOD FOR TREATING HYPERCHOLESTEROLE WITH NON-REPLACED POLYDYLYLAMINE BACKGROUND OF THE INVENTION The reabsorption of bile acids by the intestine preserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can decrease by reducing the reabsorption of bile acids. One method of reducing the amount of biliary acids reabsorbed and, therefore, reducing serum cholesterol is the oral administration of compounds that sequester bile acids and can not themselves be absorbed. The kidnapped bile acids are excreted. Compounds that have been suggested for bile acid sequestration include various ion exchange polymers. One such polymer is cholestyramine, a copolymer of divinylbenzene and tri-ethylammonium methylstyrene. For a long time, it has been recognized that this polymer is not palatable, that it is sandy and that it produces constipation. More recently, various polymers have been suggested which are characterized by hydrophobic substituents and substituted quaternary ammonium radicals on a polymeric amine backbone (Ahlers et al., U.S. Patent Nos. 5,428,112 and 5,430,110 and McTaggart et al., U.S. Patent 5,462,730, incorporated herein by reference). In some cases, these polymers have had a disappointing efficiency and require complex procedures for their manufacture. Therefore, it is still necessary to discover superior bile acid sequestrants.

Compendium of the Invention The invention relates to the unexpected discovery that a new class of ion exchange resins have better bile salt sequestration properties. The polymers, or resins, employed in the invention consist of non-absorbable and eventually crosslinked polydiallylamines. The polydiallylamines of the invention are characterized by one or more monomer units of the formulas: or a combination of these and their salts. The polymer can be characterized by the substantial absence of one or more alkylated amine monomers and / or the substantial absence of one or more trialkylammonioalkyl groups. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent. The polymer can also be characterized as being linear or branched. The invention provides an effective treatment for removing bile salts from a patient (and, thereby, reducing the patient's cholesterol level). The invention also provides the use of the polymers described herein in therapy or for the manufacture of a medicament for the treatment of hypercholesterolemia or for the sequestration of bile acids. Other features and advantages will be apparent from the following description of its preferred embodiments and the claims.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention will now be described more particularly and set forth in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The main features of the invention can be employed in various embodiments without deviating from the scope of the present invention. The invention provides a method for removing bile acids from a patient, comprising administering to the patient a therapeutically effective amount of a polymer characterized by a diallylamine monomer or repeating unit. As used herein, the term "therapeutically effective amount" refers to an amount that is sufficient to eliminate a significant amount of bile acids from the patient and, therefore, to reduce the serum cholesterol level of the patient. The patient can be an animal, for example a mammal, or a human. As described herein, the polymers used in the invention consist of non-absorbable and optionally cross-linked polydiallylamines characterized by the above formula. An important fact is that the polymers can be characterized by the substantial absence of substituted or unsubstituted alkyl substitutes on the amino group of the monomer, as obtained in the alkylation of an amine polymer. That is, the polymer can be characterized by the fact that the polymer is substantially free of alkylated amine monomers. The polymer can be a homopolymer or a copolymer.

When copolymers are manufactured with a diallylamine monomer, the comonomers are preferably inert, non-toxic and / or bile acid sequesng properties. Suitable examples of additional comonomers include substituted and unsubstituted acrylate, substituted and unsubstituted acrylamide, substituted and unsubstituted methacrylate, substituted and unsubstituted methacrylamide, allylamine, trilamylamine, allyl alcohol, substituted and unsubstituted vinylamine and substituted vinyl alcohol and not replaced. In one embodiment, the additional monomer is sulfur dioxide. Preferably, the monomers are aliphatic. More preferably, the polymer is a homopo-limer, i.e., a homopolyidially ina. Preferably, the polymer is made hydro-soluble by branching and / or crosslinking. The crosslinking agent can be characzed by functional groups that react with the amino group of the monomer. Alatively, the crosslinking group can be characzed by two or more vinyl groups undergoing polymerization of free radicals with the amine monomer. Suitable multifunctional comonomers include triallylamine, tetraallylammonium salts, bis (diallylamines) (such as alkylene-bis (diallylamines)), diacrylates, triacrylates and tetraacrilates, dimethacrylates, diacrylamides, diallylaclamide and di (methacrylamides). Specific examples include ethylenebis (diallylamine), hexamethylenebis (diallylamine), ethylene glycol di-acrylate, propylene glycol diacrylate, butylene glycol di-acrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylenebis (methacrylamide), ethylenebis (acrylamide), ethylenebis (methacrylamide), ethylidenebis (acrylamide), ethylidenebis (methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate and bisphenol diacrylate A. Other suitable multifunctional monomers include polyvinylars, such as divinylbenzene. The polymer may alatively be cross-linked by bridging units that bind amino groups on adjacent polymeric strands. Suitable bridging units include alkylene, diacylalkylene groups, diacylarene groups and straight or branched, substituted or unsubstituted alkylenebis (carbamoyl) groups. Examples of suitable bridge units include - (CH2) n- / where n is an integer from about 2 to about 20; -CH2-CH (0H) -CH2-, -C (O) CH2CH2C (O) -, -CH2-CH (OH) -O- (CH2) n-0-CH- (OH) -CH2-, where n is 2 to about 4; -C (O) - (C6H2- (COOH) 2) -C (O) - and -C (O) NH (CH2) PNHC (O) -, where p is an integer from about 2 to about 20 Examples of suitable crosslinking agents include acryloyl chloride, epichlorohydrin, butanediol diglycidyl ether, ethanedioldiglycidyl ether and dimethyl succinate. A preferred crosslinking agent is epichlorohydrin, due to its high availability and its low cost. Epichlorohydrin is also advantageous due to its low molecular weight and its hydrophilic nature, which increases the waswelling of the polyamine. The level of crosslinking makes the polymers insoluble and substantially resistant to absorption and degradation, thus limiting the activity of the polymer to the gastrointestinal tract. Therefore, the compositions are non-systemic in their activity and will lead to reduced side effects in the patient. Typically, the crosslinking agent is present in an amount of about 0.5-50% (more preferably, about 0.5-30% and, more preferably, about 2-20%) by weight, based on the weight Total monomer plus crosslinking agent. When used in non-crosslinked form, the polymers of use in the present method are preferably of a molecular weight that allows them to reach and remain in the gastrointestinal tract for a sufficient period of time to bind a significant amount of one or more acids biliary These polymers must have, therefore, a molecular weight high enough to partially or completely resist absorption by the gastrointestinal tract to other regions of the body. The resulting polymer / bile salt complex must then be excreted from the organism. Suitable linear (non-crosslinked) polymers have molecular weights ranging from about 2,000 Daltons to about 500,000 Daltons, preferably between about 5,000 Daltons and about 150,000 Daltons. Crosslinked polymers, however, are not characterized, in general, by molecular weight. The crosslinked polymers discussed herein must be sufficiently crosslinked to resist adsorption by the gastrointestinal tract.

As described above, the polymer can be administered in the form of a salt or as a partial salt. By "salt" it is meant that the nitrogen groups in all or some of the repeating units are protonated to create a positively charged nitrogen atom associated with a negative charge counter ion. Anionic counterions can be selected to minimize adverse effects on the patient, as described in more detail below. Examples of suitable counterions include Cl ", Br", CH3OSO3", HS0", S04"2, nitrate, HC03", C03"2, acetate, lactate, phosphate, hydrophosphate, methanesulfonate, fumarate, malate, pyruvate, malonate, benzoate, glucuronate, oxalate, acetylglycinate, succinate, propionate, butyrate, ascorbate, citrate, tartrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid or a phospholipid The counterions may be the same or different between For example, the reaction product can contain two different types of counterions: The polymers according to the invention can be administered orally to a patient in a dosage of about 1 mg / kg / day to about 10 g / kg / day, preferably from about 1 mg / kg / day to about 200 mg / kg / day, the particular dosage will depend on the individual patient (e.g., the patient's weight and the degree of bile salt removal required). It can be flavored or hydrated or added to a food or drink, if desired, to increase patient acceptance. Additional ingredients may also be added, such as other bile acid sequestrants, drugs to treat hypercholesterolemia, atherosclerosis or other related indications, or inert ingredients, such as artificial coloring agents. Examples of suitable forms for administration include pills, tablets, capsules and powders (for example, to sprinkle on the food). The pill, tablet, capsule or powder may be coated with a substance capable of protecting the composition from disintegration in the esophagus, but allowing the composition to be disintegrated in the stomach and mixed with the food to pass into the intestine. thin of the patient. The polymer can be administered alone or in combination with a pharmaceutically acceptable carrier substance, diluent or excipient, such as a solid, liquid or semi-solid material. Examples of suitable carriers, diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate, cellulose, for example magnesium carbonate or a phospholipid with the that the polymer can form a micelle. Polymers for use in the present method can be prepared using techniques known in the field of polymer synthesis (see, for example, Shalaby et al., Ed., Water-Soluble Polymers, American Chemical Society, Washington DC (1991) ). For example, the appropriate monomer (s) can be polymerized by methods known in the art, for example by a free radical addition process. In this case, the polymerization mixture includes a free radical initiator, such as a free radical initiator selected from those that are well known in the field of polymer chemistry. Suitable free radical initiators include azobis (isobutyronitrile), azo-bis (4-cyanovaleric acid), azobis dihydrochloride (amidinopropane), potassium persulfate, ammonium persulfate and potassium hydrogen persulfate. The free radical initiator is preferably present in the reaction mixture in an amount of between about 0.1 mole percent and about 5 mole percent relative to the monomer. The polymer can be crosslinked, for example, by including a multifunctional comonomer as a crosslinking agent in the reaction mixture. A multifunctional co-monomer can be incorporated into two or more growing polymer chains, thus crosslinking the chains. Suitable multifunctional comonomers include those discussed above.

The polymers can also be crosslinked after polymerization by reacting the polymer with one or more crosslinking agents having two or more functional groups, such as electrophilic groups, which react with amine groups to form a covalent bond. The cross-linking in this case can occur, for example, by nucleophilic attack of the amino groups of the polymer on the electrophilic groups. This results in the formation of a bridge unit that joins two or more atoms of amine nitrogen from different polymer strands. Suitable cross-linking agents of this type include compounds having two or more groups selected from acyl-X, epoxide and alkyl-X, where X is a suitable leaving group, such as a halo, tosyl, mesyl, acyl or glycidyl group. Examples of such compounds include epichlorohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethane dioldiglycidyl ether, pyromellitic dianhydride and dihaloalkane. The crosslinking agent can also be an α, β-alkylene diisocyanate, for example OCN (CH 2) pNCO, where p is an integer from about 2 to about 20. The polymer can also be crosslinked using a crosslinking agent that incorporates a group functional that is incorporated into the chain being polymerized and a second functional group that can react with amine groups in a second polymer chain. Examples include glycidyl methacrylate, glycidyl acrylate, acryloyl chloride, methacryloyl chloride, 3-bromopropyl acrylate, 3-bromopropylmethyldiallylammonium chloride and 3-chloropropyldiallylamine. The invention will now be described more specifically by the examples. Example 1 - Preparation of poly (diallylammonium chloride) Concentrated hydrochloric acid (507.0 g, 37%) was charged to a 5 L, 3-neck round bottom flask and stirred with a mechanical stirrer. The flask was cooled to < 5 ° C with an ice bath. Diallylamine (635.0 ml) was added dropwise to the hydrochloric acid under stirring over a period of three hours using an addition funnel capped with a perforated rubber partition. The temperature of the stirring solution was maintained at < 10 ° C. After the addition was complete, the ice bath was removed and the mixture allowed to warm to room temperature. Concentrated hydrochloric acid (7.3 g) was added to the solution. Water (368.7 g) was added to the solution and allowed to settle overnight. The stirred solution was purged with nitrogen gas for 30 minutes at room temperature. 2,2'-Azobis [2-amidinopropane] di-hydrochloride (6.87 g) was added as 34.4 g of a 20% aqueous solution. The solution was heated at 60 ° -80 ° C for six and a half hours. 2,2'-Azobis [2 -amidinopro-pano] (6.87 g) dihydrochloride was added as a 20% aqueous solution. The solution was stirred and heated overnight (16 hours). 2,2'-Azobis [2-amidinopropane] dichloride (6.87 g) was added as a 20% aqueous solution. The solution was stirred and heated for a further 16 hours and then cooled to room temperature. Sodium hydroxide (53.8 g) was dissolved in H0 (2156 ml). The polydiallylamine-HCl solution was then added to the sodium hydroxide solution and stirred with a mechanical stirrer until dissolved. Concentrated hydrochloric acid (49.8 g, 37%) was added. Example 2 - Synthesis of polydiallylamine A solution of 39.3 g of an aqueous solution (68% by weight) of diallylammonium hydrochloride, 5.3 g of an aqueous solution (73% by weight) of triallylamine hydrochloride and 0.5 g of water were bubbled through. , 9 g of 2,2'-azobis (2-amidinopropane) dihydrochloride with a slow stream of nitrogen for 30 minutes. While stirring, this reaction mixture was added to a solution of 7 g of polyvinyl acetate in 300 ml of toluene. The resulting mixture was stirred at room temperature for 45 minutes under a nitrogen atmosphere. While stirring, the temperature of the reaction mixture was raised to 60 ° C and maintained at this temperature for 24 hours. The reaction mixture was allowed to cool to room temperature and the polymer particles were collected by filtration. While they were in the funnel, the filtered particles were successively washed with 300 ml of toluene and 500 ml of methanol. The polymer particles were suspended in 500 ml of methanol, stirred for 50 minutes and filtered. The particles were then suspended in 400 ml of deionized water, stirred for 30 minutes and filtered.The filtered particles were dried at 60 ° C for 24 h to obtain 15 g of the polymer Example 3 - Crosslinked polydiallylamine Crosslinked the polymer solution of Example 1 at 30 mol% as follows: Epichlorohydrin (31.61 ml) was added to 900.0 g of the neutralized polymer solution in a glass beaker, stirred with a magnetic stirrer and covered with polyvinyl film The gel was allowed to cure for 22 hours The solid gel was then crushed using a kitchen crusher The ground polymer was washed as a static bed using a large plastic paper-coated Buchner funnel A second piece of filter paper, punched with holes, was placed on the top of the polymer cake to prevent the cake from being altered when the wash water was added. ionized fresh (14 L) to the top of the cake and drained under vacuum. The washed polymer was then transferred to glass drying trays and dried in a forced air oven at 60 ° C for several days. The final dry weight was 176.2 g. Example 4 - Crosslinked Polydiallylamine Using the same procedure as in Example 3, the neutralized polymer solution was crosslinked at 20 mol%. Epichlorohydrin (21.07 ml) was added to 900.0 g of the neutralized polymer solution. The final dry weight was 163.3 g. Example 5 - Crosslinked Polydiallylamine Using the same procedure as in Example 3, the neutralized polymer solution was crosslinked at 10 mol%. Epichlorohydrin (10.54 ml) was added to 900.0 g of the neutralized polymer solution. The final dry weight was 164.2 g. Example 6 - Crosslinked Polydiallylamine Using the same procedure as in Example 3, the neutralized polymer solution was crosslinked to 4.5 mol%. Epichlorohydrin (4.74 ml) was added to 900.0 g of the neutralized polymer solution. The final dry weight was 176.2 g. Example 7 - Copolymer of diallylamine and methylenebisacrylamide A solution of diallyl ammonium chloride was heated (73.53 g of a 68% aqueous solution), methylenebisacrylamide (2.93 g, 0.019 mol), 2,2'-azobis (2-amidinopropane) dihydrochloride (V50) (0.5 g) and water (27 ml) at 70 ° C under a nitrogen atmosphere. Water (100 ml) was added after 15 minutes of reaction. An additional 0.5 g of V50 was added after 3 hours and again after a further 4 hours. After maintaining the reaction at 70 ° C for a total of 72 h, it was cooled to room temperature. The resulting material was filtered and washed with 2 M NaCl (400 mL) and filtered and washed with water (2.5 L) and filtered again. The washed polymer was dried at 60 ° C in a forced air oven to give 18.8 g of a solid (0.36 g / g yield, IPS = 18.4). Example 8 - Copolymer of diallylamine and acrylamide A solution of diallylammonium chloride (73.53 g of 68% aqueous solution), methylenebis-acrylamide (2.93 g, 0.019 mol), 2,2 'dihydrochloride was heated. azobis (2-amidinopropane) (0.5 g) and water (27 ml) at 70 ° C under a nitrogen atmosphere for 3 days. Water (100 ml) was added after the first 15 minutes of reaction. 2,2'-Azobis (2-amidino-propane) dihydrochloride (0.5 g) was added after 3 hours and 7 hours. The resulting material was filtered and washed with 2 M NaCl (400 mL) and water (2.5 L). The washed polymer was dried at 60 ° C in a forced air oven to give 18.8 g of a solid.

Example 9 - Copolymer of diallylamine, acrylamide and methylenbuisacrylamide A solution of diallyl ammonium chloride was heated (14.7 g of a 68% aqueous solution), acrylamide (5.33 g), methylenebisacrylamide (2.31 g), MeOH (50 ml) and 2,2-dichlorohydrate-azobis (2-amidinopropane) ) (0.07 g of an 18.8% solution in water) at 65 ° C under a nitrogen atmosphere for 20 hours. The resulting material was suspended in methanol (500 mL), stirred for 15 minutes and filtered. This washing with methanol was repeated twice more. The washed polymer was suspended in water (500 ml) and this mixture was acidified with concentrated HCl to pH 2.4. Filtration and drying at 6-0 ° C in a forced air oven gave 9.8 g of a solid.

Example 10 - Diallylamine copolymer, a functionalized acrylic ester and an acrylic ester crosslinking monomer A solution of diallylammonium chloride (14.7 g of a 68% aqueous solution), 2-hydroxyethyl methacrylate (9, 76 g), ethylene glycol dimethacrylate (2.97 g), MeOH (25 ml) and 2,2'-azobis (2-amidinopropane) dihydrochloride (0.07 g of a 18.8% aqueous solution) at 65 g. ° C under a nitrogen atmosphere for 20 hours. The resulting material was suspended in methanol (500 mL), stirred for 15 minutes and filtered. The polymer was similarly washed three times with water (500 ml). This methanol wash and filtration were repeated twice more. The washed polymer was suspended in water (500 ml) and this mixture was acidified with concentrated HCl to pH 2.1. Filtration and drying at 60 ° C in a forced air oven gave 13.9 g of a solid. Example 11 - Diallylamine copolymer, functionalized acrylic ester and acrylic ester crosslinking monomer A solution of diallylammonium chloride (22.06 g of a 68% aqueous solution), te-trahydrofurfuryl methacrylate ( 18.72 g), ethylene glycol dimethacrylate (4.36 g) and 2,2'-azobis (2-amidinopropane) dihydrochloride (2.03 g of a 18.8% aqueous solution) at 65 ° C under a Nitrogen atmosphere for 24 hours. The resulting material was suspended in methanol (300 mL), stirred for 15 minutes and filtered. This washing with methanol and filtration were repeated twice more. The polymer was washed in a similar manner three times with water (500 ml). The material was suspended in water (500 ml) and this mixture was acidified with concentrated HCl to pH 2.0. Filtration and drying at 60 ° C in a forced air oven gave 19.9 g of a solid.

Example 12 - Copolymer of diallylamine and glycidyl methacrylate A solution of diallylammonium chloride (29, 42 g of a 68% aqueous solution), glycidyl methacrylate (2.13 g), MeOH (25 ml) and 2,2'-azobis (2-amidinopropane) dihydrochle (1.18 g of an aqueous solution at 18.8%) at 65 ° C under a nitrogen atmosphere for 12 hours. After cooling to room temperature, methanol (25 ml) was added and the pH of the solution was adjusted to 10 with the addition of 50% aqueous NaOH and allowed to stir at room temperature. The reaction solution was converted to a solid mass after about 2 hours and allowed to stand for 22 hours. The resulting gel was suspended in MeOH (300 mL), stirred and filtered. This washing with methanol and filtration were repeated twice more. The polymer was suspended in water (1 L). Concentrated HCl was added to this suspension to a pH of 2.0 and stirred for 0.5 hour. Filtration and drying in a forced air oven at 60 ° C gave 6.0 g of a solid.

Example 13 - Copolymer of allylamine, diallylamine, tri-allylamine and a bis (diallylamino) alkylene salt A solution of allyl ammonium chloride (25.0 g of a 60% aqueous solution), diallylammonium chloride was heated (66.81 g of a 67% aqueous solution), triallylammonium chloride (40.87 g of a 68% aqueous solution), 1,6-bis (diallylmethylammonium) hexane dibromide (5.0 g) and dihydrochloride of 2, 2'-azobis (2-amidinopropane) (4.28 g of a 20% aqueous solution) at 55 ° C under a nitrogen atmosphere for 18 hours and at 80 ° C for 2 hours. After cooling to room temperature, the gel was suspended in MeOH (500 mL), stirred for 15 minutes and filtered. This method was repeated. The polymer was suspended in water (1.0 L) and stirred for at least 15 minutes and filtered. After drying in a forced air oven at 60 ° C, 31.9 g of a solid were isolated. Example 14 - Allylamine and diallylamine copolymer A solution of allyl ammonium chloride (54.71 g of a 57% aqueous solution), diallylammonium chloride (132.96 g of a 67% aqueous solution) was heated. and 2, 2'-azobis (2-amidinopropane) dihydrochloride (6.01 g of a 20% aqueous solution) at 55 ° C under a nitrogen atmosphere for 36 hours. Another portion of 2,2'-azobis (2-amidinopropane) dihydrochloride (6.01 g of a 20% aqueous solution) was added after the first 18 hours. After cooling to room temperature, the solution was slowly added to IPA (3 L) and the precipitate was washed, after decanting the IPA layer, with IPA (3 L) and filtered. The precipitate was dried in a forced air oven at 60 ° C to obtain 106.9 g of a solid. Example 15 - Copolymer of allylamine, diallylamine and a bis (diallylamino) alkylene A solution of allylammonium chloride (27.36 g of a 57% solution), diallylammonium chloride (66.48 g of an aqueous solution) was heated. 67%), 1,6-bis (diallylmethylammonium) hexane dibromide (10.0 g) and 2,2'-azobis (2-amidinopropane) dihydrochloride (3.01 g of a 20% aqueous solution) ) at 55 ° C under a nitrogen atmosphere for 36 hours. Another portion of 2,2'-azobis (2-amidinopropane) dihydrochloride (3.01 g of a 20% aqueous solution) was added after the first 18 hours. A gel formed after approximately 24 hours of heating. After cooling to room temperature, this material was washed with MeOH (500 mL) and filtered three times, as described above. The polymer was then suspended and washed with water (2.5 L). After filtration, the wet material was dried in a forced air oven at 60 ° C to obtain 24.8 g of a solid. Example 16 - In vivo tests. Syrian Golden Syrian hamsters were housed in cages in the shape of a shoebox and acclimatized for approximately 1 week in our animal house. The animals were fed with rodent feed (brown color) and water ad libitum. The hamsters were then transferred to metabolism cages and housed individually. After 24 hours of fasting (water ad libitum), the animals were presented with a purified diet based on ca-seine (white color) with 10% added fat plus the drug to be evaluated. Fecal matter was collected 9 hours after presenting the casein-based diet and for an additional 39 hours. White stools were lyophilized (diet based on casein containing drug) and ground to a homogeneous powder. One gram of the crushed feces was extracted in a solution consisting of methanol and 500 mM aqueous NaOH (4: 1, v / v) at 100 ° C and 1,500 psi for 15 minutes. An aliquot of 500 μl of the extract was evaporated and reconstituted in 1,500 μl of calf serum: 0.9% saline solution (1: 1) and analyzed enzymatically, using a bile acid assay kit (Sigma Chemical Co., St. Louis, MO) for the concentration of bile acids. Table This example shows that the crosslinked polydiallylamine is a highly potent bile acid sequestrant, with a greater in vivo activity than the current commercial products, Colestipol and Colestyramine. EQUIVALENTS Those skilled in the art will know, or may determine, using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. These and all other equivalents are intended to be covered by the following claims.

Claims (20)

Claims

1. A method for removing bile salts from a patient, comprising administering to said patient a therapeutically effective amount of a polydiallylamine polymer and its salts, which polymer is characterized in that the polymer is substantially free of alkylated amine monomers.

2. The method of Claim 1, wherein said polymer is crosslinked by means of a multifunctional crosslinking agent, which agent is present in an amount of about 0.5-50% by weight, based on the combined weight of monomer and crosslinking agent.

3. The method of Claim 2, wherein said crosslinking agent is present in an amount of about 2.5-20% by weight, based on the combined weight of monomer and crosslinking agent.

4. The method of Claim 2, wherein said crosslinking agent consists of epichlorohydrin.

5. The method of Claim 2, wherein said crosslinking agent is a bis (diallylammonium) di-alkylene ion.

6. The method of Claim 1, wherein the polymer is a homopolymer.

7. A method of Claim 1, wherein the polymer is a copolymer.

8. A method of Claim 7, wherein the copolymer consists of the diallylamine, allylamine and triallylamine monomers.

9. A method of Claim 7, wherein the copolymer consists of the diallylamine and allylamine monomers.

10. A method for removing bile salts from a patient, comprising administering to said patient a therapeutically effective amount of a polydiallylamine polymer and its salts, which polymer is characterized in that the polymer is free of alkylated amine monomers.

11. A polymer of polydiallylamine and its salts, substantially free of alkylated amine monomers for use in medical treatment.

12. The use of a polydiallylamine polymer and its salts, the polymer of which is characterized in that the polymer is substantially free of alkylated amine monomers, for the manufacture of a bile acid sequestrant.

13. The use of Claim 12, wherein the polymer is crosslinked by means of a multifunctional crosslinking agent, which agent is present in an amount of about 0.5-50% by weight, based on the combined weight of monomer and crosslinking agent.

14. The use of Claim 13, wherein said crosslinking agent is present in an amount of about 2.5-50% by weight, based on the combined weight of monomer and crosslinking agent.

15. The use of Claim 13, wherein said crosslinking agent consists of epichlorohydrin.

16. The use of Claim 13, wherein said crosslinking agent is a bis (diallylammonium) dialkylene ion.

17. The use of Claim 13, wherein the polymer is a homopolymer.

18. The use of Claim 13, wherein the polymer is a copolymer.

19. The use of Claim 18, wherein the copolymer consists of the monomers diallylamine, allylamine and triallylamine.

20. The use of Claim 18, wherein the copolymer consists of the diallylamine and allylamine monomers.