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WO1994027619A1 - Procede permettant d'ajuster la concentration ionique chez un patient et composition a cet effet - Google Patents

Procede permettant d'ajuster la concentration ionique chez un patient et composition a cet effet Download PDF

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Publication number
WO1994027619A1
WO1994027619A1 PCT/US1994/004538 US9404538W WO9427619A1 WO 1994027619 A1 WO1994027619 A1 WO 1994027619A1 US 9404538 W US9404538 W US 9404538W WO 9427619 A1 WO9427619 A1 WO 9427619A1
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Prior art keywords
ions
polymers
positively charged
composition
sodium
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Ceased
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PCT/US1994/004538
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English (en)
Inventor
W. Harry Mandeville, Iii
Stephen Randall Holmes-Farley
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GelTex Inc
Geltex Pharmaceuticals Inc
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GelTex Inc
Geltex Pharmaceuticals Inc
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Priority to AU68188/94A priority Critical patent/AU6818894A/en
Publication of WO1994027619A1 publication Critical patent/WO1994027619A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795

Definitions

  • This invention relates to adjusting ion concentration in a patient.
  • Ion exchange resins which, when ingested, remove ions via the digestive tract are known.
  • One such commercially available product is Kayexalate®, which is the sodium salt of a sulfonated polystyrene resin. When ingested, Kayexalate® exchanges its sodium ions in part for potassium ions and other cations present in the body. The resulting product (which is now the potassium salt of a sulfonated polystyrene resin) is then excreted from the body, thereby removing excess potassium ions.
  • the invention features a method of adjusting the concentration of selected ions in a patient by ion exchange that includes administering to the patient a therapeutically effective amount of one or more crosslinked polymers that are non-toxic and stable once ingested.
  • the polymers include units having one or more fixed (i.e., permanent) negatively charged sulfonate (-SO 3 -) , sulfate (-OS0 3 ⁇ ) , phosphonate (-P0 3 2 ⁇ , -P0 3 H") , phosphate (-0P0 3 2 ⁇ , -OP0 3 H " ) , onocarboxylate (-C0 2 ”) , or boronate (-B0 2 H " , -B0 2 2” ) ions, and positively charged counterions other than hydrogen associated with these negatively charged ions that are exchangeable with ions in the gastrointestinal tract.
  • the exchangeable counterions may be the same as, or different from, each other.
  • the polymer may contain two different types of counterions, both of which are exchanged for ions in the gastrointestinal tract. More than one polymer, each having different counterions associated with the fixed charges, may be administered as well.
  • the polymers are non-constipating and non-gritty (when measured relative to polymers such as Kayexalate® that are the sodium salts of sulfonated polystyrene resins) such that irritation to the gastrointestinal tract upon ingestion is minimized.
  • the invention features a method of adjusting the concentration of selected ions in a patient by ion exchange that includes administering to the patient a therapeutically effective amount of one or more crosslinked polymers that are non-toxic and stable once ingested in which the polymers include units having one or more fixed (i.e., permanent) negatively charged polycarboxylate ions and positively charged counterions other than hydrogen or ammonium associated with these negatively charged ions that are exchangeable with ions in the gastrointestinal tract.
  • the exchangeable counterions may be the same as, or different from, each other.
  • the polymer may contain two different types of counterions, both of which are exchanged for ions in the gastrointestinal tract.
  • More than one polymer each having different counterions associated with the fixed charges, may be administered as well.
  • the polymers are non-constipating and non-gritty (when measured relative to polymers such as Kayexalate® that are the sodium salts of sulfonated polystyrene resins) such that irritation to the gastrointestinal tract upon ingestion is minimized.
  • non-toxic it is meant that when ingested in therapeutically effective amounts neither the polymers nor the ions released into the body upon ion exchange are harmful.
  • the ions released into the body are actually beneficial to the patient.
  • the exchangeable cations are natural nutrients such as amino acids, choline, and calcium.
  • stable it is meant that when ingested in therapeutically effective amounts the polymers do not dissolve or otherwise decompose to form potentially harmful by-products, and remain substantially intact so that they can transport ions following ion exchange out of the body.
  • the positively charged counterions include both non-metallic ions and metallic ions.
  • suitable non-metallic ions include ammonium, alkyl ammonium (e.g., containing between 1 and 4 ⁇ - ⁇ alkyl groups, trimethyl or triethyl ammonium), hydroxyalkylammonium (e.g., hydroxyethylammonium) , hydroxyalkyl amino (e.g., hydroxyethyl amino) , choline, taurine, carnitine, guanidine, creatine, adenine, and amino acids (e.g., glycine, lysine, serine, arginine, alanine, histidine, or aspartic acid), or derivatives thereof (e.g., alkyl esters and amides) having a net positive charge.
  • suitable metallic ions include sodium, potassium, calcium, and magnesium.
  • R 1 , R 2 , and R 3 independently, is H or a lower (e.g., ( ⁇ -0 5 ) alkyl group (e.g., methyl).
  • R 1 is H
  • R 2 is CH 3
  • R 3 is CH 3
  • at least some the positively charged counterions include choline, sodium, hydroxyaIky1ammonium (e.g., ethanolammoniu ) , or an amino acid (or derivative thereof) .
  • n is an integer
  • M + is an exchangeable counterion
  • each R 1 and R 2 independently, is H or a lower (e.g., C ⁇ Cg) alkyl group (e.g., methyl).
  • at least some of the positively charged counterions include choline, sodium, hydroxylalkylammoniu (e.g., ethanolammonium), or an amino acid (or derivative thereof) .
  • a third example is a polymer characterized by a repeat unit having the formula
  • n is an integer
  • M + is an exchangeable counterion
  • each R 1 and R 2 independently, is H or a lower (e.g., C 1 -C 5 ) alkyl group (e.g., methyl).
  • at least some of the positively charged counterions include choline, sodium, hydroxyalkylammonium (e.g., ethanolammonium), or an amino acid (or derivative thereof) .
  • n is an integer
  • M + is an exchangeable counterion
  • each R 1 and R 2 independently, is H or a lower (e.g., ⁇ -C 8 ) alkyl group (e.g., methyl).
  • at least some the positively charged counterions include choline, sodium, hydroxyalkylammonium (e.g., ethanolammonium), or an amino acid (or derivative thereof) .
  • n is an integer
  • M + is an exchangeable counterion
  • each R 1 and R 2 independently, is H or a lower (e.g., C 1 -C 5 ) alkyl group (e.g., methyl).
  • at least some the positively charged counterions include choline, sodium, hydroxyalkylammonium (e.g., ethanolammonium), or an amino acid (or derivative thereof) .
  • a fifth example is ethylene-maleic anhydride copolymer in which at least some of the positively charged counterions include choline, sodium, hydroxyalkylammonium (e.g. , ethanolammonium) , or an amino acid (or derivative thereof) .
  • the positively charged counterions include choline, sodium, hydroxyalkylammonium (e.g. , ethanolammonium) , or an amino acid (or derivative thereof) .
  • the invention also features therapeutic compositions that include a therapeutically effective amount of the above-described polymers.
  • the polymers are particularly useful, e.g., for adjusting the concentration of potassium ions in a patient.
  • the invention provides an effective treatment for adjusting the concentration of one or more selected ions in a patient by ion exchange.
  • the compositions are non- toxic and stable when ingested in therapeutically effective amounts. They are also tasteless (in the absence of added flavoring) and odorless, as well as being non-constipating and non-gritty.
  • Preferred polymers have the formulae set forth in the Summary of the Invention, above.
  • the polymers are crosslinked, making them insoluble and thereby limiting their activity to the gastrointestinal tract only. Thus, the polymers are non-systemic in their activity and will lead to reduced side-effects in the patient.
  • the polymers feature negatively charged fixed charges and positively charged exchangeable counterions (other than hydrogen) associated with these fixed charges. They are useful for altering the concentration of selected positively charged ions in the body, e.g., sodium, potassium, calcium, ammonium, copper, aluminum, and toxic heavy metal ions (e.g., cadmium, nickel, mercury, lead, and radioactive elements) . Examples of suitable negatively charged fixed charges and positively charged counterions are set forth in the Summary of the Invention, above.
  • the polymers may contain additional co-monomers as well.
  • the co-monomers may contain no fixed charges or they may feature other types of fixed charges and associated counterions (which may be, e.g., hydrogen ions).
  • suitable co- monomers include, e.g., acrylamide and methacrylamide.
  • AMPS poly-2-acrylamido-2-methylpropane sulfonic acid
  • M + is an exchangeable counterion other than hydrogen
  • the negatively charged fixed charges are the sulfonate groups (which are covalently attached to the polymer backbone) .
  • the polyacrylamide-based backbone contributes to the non-toxicity of these polymers when ingested in therapeutically effective amounts.
  • Another example of a preferred resin within this class includes salts of polyvinylsulfonic acid having the following formula (where M + is an exchangeable counterion other than hydrogen) :
  • the negatively charged fixed charges are sulfonate groups (which are covalently attached to the polymer backbone) .
  • the negatively charged fixed charges are monocarboxylate groups (which are covalently attached to the polymer backbone) .
  • a fourth example of a preferred resin within this class includes salts of polyvinylphosphonic acid, or copolymers of vinyl phosphonic acid having the following formula (where M + is an exchangeable counterion other than hydrogen) :
  • a fifth example of a preferred resin includes salts of polyitaconic acid, or copolymers of polyitaconic acid having the following formula (where M + is an exchangeable counterion other than hydrogen or ammonium) :
  • the negatively charged fixed charges are two carboxylate groups (which are covalently attached to the polymer backbone) .
  • a sixth example of a preferred resin includes salts of ethylene-maleic anhydride copolymer (where M + is an exchangeable counterion other than hydrogen or ammonium) .
  • the negatively charged fixed charges are two carboxylate groups (which are covalently attached to the polymer backbone) .
  • counterion will depend in part on the ion concentration being adjusted.
  • choline has been found to be an effective exchangeable counterion.
  • the counterion may also be selected based upon its ability to supply needed ions (e.g., ions which are nutrients) to the body.
  • ions e.g., ions which are nutrients
  • counterions such as amino acids, choline, and calcium are natural nutrients; thus, the invention provides a convenient way of supplying these beneficial materials to the patient while at the same time removing undesirable ions.
  • any potassium ions exchanged for choline ions will be replenished by potassium ions from polymer exchanged for sodium ions.
  • the polymers are crosslinked, preferably by adding a crosslinking co-monomer to the reaction mixture during polymerization.
  • suitable crosslinking co- monomers are diacrylates and dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate, polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate) , methylene bisacrylamide, methylene bismethacrylamide, ethylene bisacrylamide, ethylene bismethacrylamide, ethylidene bisacrylamide, N- allylacrylamide, divinyl benzene, bisphenol A dimethacrylate, and bisphenol A diacrylate.
  • the amount of crosslinking co-monomer is typically between 2.5 and 25 weight %, based upon combined weight of crosslinking co-monomer and other monomers, with 10%
  • the resins are prepared by generating the monomer salt in situ, followed by polymerization in the presence of crosslinking co- monomer and initiator, and purification to yield the product resin.
  • the monomer salt is combined with initiator and crosslinking co- monomer, polymerized, and then purified.
  • acryloyl chloride (18.10 g, 0.200 mol) and tetrahydrofuran (150 mL) .
  • the resulting solution was cooled to +5°C and a solution of ethylenediamine (12.20 g, 0.200 mol) in tetrahydrofuran (100 mL) was added dropwise to the acryloyl chloride solution over a period of two hours, keeping the temperature between +5° and +10°C. After the addition was completed, the mixture was stirred for an additional five minutes and then filtered.
  • ethylenediamine monoacrylamide monohydrochloride 15.06 g, 0.100 mol
  • water 150 mL
  • Potassium hydroxide 6.40 g, 0.100 mol
  • the solution was cooled in an ice bath.
  • acrylamidomethylpropane sulfonic acid (AMPS) (51.8 g, 0.250 mol), methylene bisacrylamide (5.8 g, 10 wt%) , and distilled water (200 mL)
  • AMPS acrylamidomethylpropane sulfonic acid
  • methylene bisacrylamide 5.8 g, 10 wt%)
  • distilled water 200 mL
  • the mixture was stirred magnetically to effect dissolution.
  • the resulting solution was then covered with Parafilm®, stirred magnetically, and degassed by bubbling nitrogen through it for 15 minutes.
  • a thermometer inserted through the Parafilm® was used to measure the reaction temperature.
  • reaction mixture was allowed to stand overnight. In the morning, it was divided into four equal portions. One portion was placed in a blender and ethanol (650 mL) added to it. The resulting mixture was blended on high for a few seconds and then stirred on low for 5 minutes to dehydrate the gel. The resulting dehydrated gel was allowed to settle and the solvent decanted.
  • the blender procedure was repeated for each portion of the reaction mixture. All four portions were then combined in the blender and 1000 mL of ethanol added was added to make a total volume of 1300 mL. The resulting mixture was stirred for 10 minutes in the blender, after which the gel was allowed to settle. Next, the solvent was decanted and an additional 600 mL of ethanol added. The mixture was then stirred for 5 minutes and again allowed to settle, after which the last trituration was repeated. The product was then filtered, washed with ethanol, and vacuum dried to yield 73.3 g of crosslinked polymer.
  • acrylamidomethylpropane sulfonic acid (AMPS) (51.8 g, 0.250 mol), choline chloride (34.9 g, 0.250 mol) and ethanol (95%, denatured) .
  • AMPS acrylamidomethylpropane sulfonic acid
  • choline chloride (34.9 g, 0.250 mol)
  • ethanol 95%, denatured
  • Sodium chloride was then filtered off (4.1 g recovered, 28% of theoretical) and methylene bisacrylamide (MBA) (5.8 g, 10 wt% based upon combined weight of AMPS and MBA) was added to the ethanolic solution.
  • MSA methylene bisacrylamide
  • the ethanol was then removed in vacuo using a rotary evaporator, after which the concentrate was quickly transferred to a 600 mL beaker using 250 mL of distilled water to aid the transfer; the water also acted as a solvent for the subsequent polymerization.
  • a catalyst consisting of potassium persulfate (0.7 g, 2.5 mmol) and sodium metabisulfite (0.7 g, 3.5 mmol) was added to the solution with stirring as solids. The reaction mixture gelled in two minutes.
  • reaction mixture was allowed to stand overnight. In the morning, it was divided into four equal portions. One portion was placed in a blender and ethanol (650 mL) added to it. The resulting mixture was blended on high for a few seconds and then stirred on low for 5 minutes to dehydrate the gel. The resulting dehydrated gel was allowed to settle and the solvent decanted.
  • acrylamidomethylpropane sulfonic acid (AMPS) (51.8 g, 0.250 mol) and distilled water (300 mL) .
  • AMPS acrylamidomethylpropane sulfonic acid
  • distilled water 300 mL
  • Methylene bisacrylamide 5.8 g, 10 wt% was then added to the solution, after which the resulting mixture was covered with Parafilm®, stirred magnetically, and degassed by bubbling nitrogen through it for 15 minutes.
  • a thermometer inserted through the Parafilm® was used to measure the reaction temperature.
  • a catalyst solution prepared by combining potassium persulfate (0.7 g, 2.5 mmol) in distilled water (30 mL) and sodium metabisulfite (0.7 g, 3.5 mmol) in distilled water (5 mL) was added to the solution all at once.
  • the exothermic polymerization proceeded almost immediately.
  • the initial rate of temperature rise was 5.5°C/min and the maximum temperature achieved was 37°C.
  • reaction mixture was allowed to stand over the weekend. It was then transferred to a blender and ethanol (800 mL) was added to it. The mixture was blended on high for a few seconds and then stirred on low for 5 minutes. The product was apparently swollen by ethanol since at this point it had not dehydrated.
  • the ethanol slurry was removed from the blender, divided into two equal portions (due to a limitation in blender volume) , and an additional 400 mL of ethanol was added to each portion. Each portion was then blended separately to yield a sticky mass. The solvent was then decanted from the sticky mass and more ethanol (400 mL) was added to each portion. Each resulting portion was blended on high for a few seconds and then stirred on low for 5 minutes, after which each portion was filter, washed with ethanol, and vacuum dried to yield a combined total of 53.5 g of crosslinked polymer.
  • the polymer had an equivalent weight of 254.7, corresponding to a functional density of 3.926 equiv/g.
  • acrylamidomethylpropane sulfonic acid (18.0 g)
  • ethylidenebisacrylamide 2.0 g, 10 wt%)
  • distilled water 50 mL
  • a solution containing sodium hydroxide 5 g
  • distilled water 10 mL
  • the resulting mixture was covered with Parafilm®, stirred magnetically, and degassed by bubbling nitrogen through it for 15 minutes. A thermometer inserted through the Parafilm® was used to measure the reaction temperature.
  • reaction mixture was allowed to stand overnight. It was then transferred to a blender and 2- propanol (150 mL) was added to it. The mixture was blended on high for a few seconds and then stirred on low for 5 minutes. The solvent was then decanted and another 200 mL of 2-propanol was added. The blending and decanting procedure was repeated two more times, with 200 mL of 2-propanol being added each time. The resulting slurry was then filtered, washed with 2-propanol, and vacuum dried to yield 26.2 g of polymer.
  • acrylamidomethylpropane sulfonic acid (AMPS) (27 g) and distilled water (54 mL) .
  • AMPS acrylamidomethylpropane sulfonic acid
  • a solution containing sodium hydroxide (6 g) and distilled water (10 mL) was added dropwise to the AMPS solution with pH monitoring and stirring until a pH of 7.0 was attained.
  • the resulting solution was then added to a blender, after which 2-propanol (208 mL) and ethylidenebisacrylamide (3.0 g, 10 wt%)) were added.
  • the mixture was stirred slowly in the blender to dissolve the crosslinking agent. It was then degassed for 15 minutes with nitrogen.
  • acrylamido-2- methylpropane sulfonic acid (20.7 g, 0.100 mol) and distilled water (160 mL) .
  • the solution was stirred magnetically and calcium carbonate (5.0 g, 0.050 mol) was added with pH monitoring. The addition of calcium carbonate was stopped when a slight trace of the material did not dissolve. The final pH of the mixture was 4.93.
  • 2.50 g of the crosslinking agent methylenebisacrylamide (MBA) was added and the solution was warmed to 40°C to effect dissolution. During the warming period, the solution was degassed with nitrogen.
  • the catalyst consisting of potassium persulfate (0.2 g) and sodium metabisulfite (0.2 g) .
  • the reaction exothermed from 45°C to 49°C, and then gelled over the course of 30 seconds.
  • the resulting gel was allowed to harden overnight.
  • the gel was transferred to a blender and 400 mL of isopropanol was added. The mixture was then blended on high for a few seconds, after which it was stirred on low for 5 minutes. Next, the solvent was decanted and the blending and decanting procedure was repeated two more times. The final mixture was then filtered, washed with isopropanol, and vacuum dried to afford 28.98 g of polymer.
  • the catalyst consisting of potassium persulfate (0.2 g) and sodium metabisulfite (0.2 g) .
  • the reaction exothermed from 37°C to 42°C, and then gelled over the course of 75 seconds. The resulting gel was allowed to harden overnight.
  • the gel was transferred to a blender and 400 mL of isopropanol was added. The mixture was then blended on high for a few seconds, after which it was stirred on low for 5 minutes. Next, the solvent was decanted and the blending and decanting procedure was repeated two more times. The final mixture was then filtered, washed with isopropanol, and vacuum dried to afford 36.11 g of polymer.
  • acrylamido-2- methylpropane sulfonic acid (20.7 g, 0.100 mol), lysine (14.62 g, 0.100 mol), methylenebisacrylamide (2.30 g) , and distilled water (180 mL) .
  • the solution was warmed to 37°C to effect dissolution. During the warming period, the solution was degassed with nitrogen.
  • the catalyst consisting of potassium persulfate (0.2 g) and sodium metabisulfite (0.2 g) .
  • the reaction exothermed from 37°C to 41°C, and then gelled over the course of 60 seconds.
  • the resulting gel was allowed to harden for four hours.
  • the gel was transferred to a blender and 400 mL of isopropanol was added. The mixture was then blended on high for a few seconds, after which it was stirred on low for 5 minutes. Next, the solvent was decanted and the blending and decanting procedure was repeated two more times.
  • acrylamido-2- methylpropane sulfonic acid (20.7 g, 0.100 mol)
  • serine 10.50 g, 0.100 mol
  • methylenebisacrylamide 2.30 g
  • distilled water 180 mL
  • the catalyst consisting of potassium persulfate (0.2 g) and sodium metabisulfite (0.2 g) .
  • the reaction exothermed from 34°C to 39°C, and then gelled over the course of 3 minutes.
  • the resulting gel was allowed to harden overnight.
  • the gel was transferred to a blender and 800 mL of isopropanol was added. The mixture was then blended on high for a few seconds, after which it was stirred on low for 5 minutes.
  • the solvent was decanted and the blending and decanting procedure was repeated two more times using 400 mL of isopropanol each time. The final mixture was then filtered, washed with isopropanol, and vacuum dried to afford 38.23 g of polymer.
  • acrylamido-2- methylpropane sulfonic acid (20.7 g, 0.100 mol), alanine (8.91 g, 0.100 mol), methylenebisacrylamide (2.30 g) , and distilled water (180 mL) .
  • the solution was warmed to 34°C to effect dissolution. During the warming period, the solution was degassed with nitrogen.
  • the catalyst consisting of potassium persulfate (0.2 g) and sodium metabisulfite (0.2 g) .
  • the reaction exothermed from 34°C to 38°C, and then gelled over the course of 2.5 minutes. The resulting gel was allowed to harden overnight.
  • the gel was transferred to a blender and 1000 mL of isopropanol was added. The mixture was then blended on high for a few seconds, after which it was stirred on low for 5 minutes. Next, the solvent was decanted and the blending and decanting procedure was repeated two more times using 400 mL of isopropanol each time. The final mixture was then filtered, washed with isopropanol, and vacuum dried to afford 29.36 g of polymer.
  • Methylenebismethacrylamide (0.5 g) and AIBN (0.1 g) were added and the mixture was heated to reflux under nitrogen. The mixture was refluxed for six hours under nitrogen and then allowed to cool to room temperature.
  • Denatured ethanol (100 mL) was added and the solution stirred for 5 minutes. The solid suspended in the ethanol was collected by filtration. The collected solid was suspended in 500 mL of water and stirred for 20 minutes and then centrifuged. The solid residue was collected and vacuum dried to afford 1.53 g of polymer.
  • the polymer was suspended in water (100 mL) and after stirring for 5 minutes, methanol (100 mL) was added. The solution was allowed to settle and the clear liquid was poured off to leave a white solid. The solid was dispersed in 500 mL of water and stirred for 40 minutes. Methanol (500 mL) was added and the solids were collected by centrifugation. The solids were vacuum dried to afford 4.68 g of polymer.
  • methylenebisacrylamide 0.5 g
  • Exposure to UV light was at room temperature for 18 h. This method afforded 5.42 g of polymer.
  • the liquid was combined with methylenebisacrylamide (5.3 g) in a 1 L reaction kettle and warmed slightly to encourage dissolution (complete dissolution was not attained) .
  • the kettle was evacuated and exposed to UV light (365 nm; -7000 mW/cm2) for 72 h.
  • Dry solid poly(sodium vinyl sulfonate) (4.0 g made by the Ion Exchange Method) was ground in an electric coffee grinder and sieved to afford 3.61 g of -80/+200 mesh particles. These particles were suspended in 400 mL of 1 M aqueous choline chloride and stirred for 2 h. The solid was collected by centrifugation and the suspension/centrifugation process repeated twice more. The solid was the vacuum dried to afford 6.82 g of crude polymer.
  • the crude polymer was suspended in 500 mL of water, stirred for 2 h, and the solid collected by filtration. This process was repeated with a second batch of 500 mL of water, and the collected solids were vacuum dried to afford 4.05 g of polymer. Analysis of the product indicated that it contained less than 0.1% sodium by weight.
  • the strongly exothermic polymerization proceeded almost immediately.
  • the reaction gelled after 1 minute.
  • the reaction mixture was allowed to stand overnight. In the morning, it was transferred to a blender and methanol (350 mL) was added. The resulting mixture was blended on high for a few seconds. It was then decanted and an additional 400 mL of methanol was added. The resulting mixture was then blended on high for a few seconds and then on low for 5 minutes.
  • the resulting granular, dehydrated polymer was filtered, washed with methanol, and air-dried to yield 44.6 g of crosslinked polymer.
  • the polymers according to the invention may be administered orally to a patient in a dosage of about 1 mg/kg/day to about 10 g/kg/day; the particular dosage will depend on the individual patient (e.g., the patient's weight and the extent of ion addition or removal required) .
  • the polymer may be administrated either in hydrated or dehydrated form, and may be flavored if necessary to enhance patient acceptability; additional ingredients such as artificial coloring agents may be added as well.
  • suitable forms for administration include pills, tablets, capsules, and powders (for sprinkling on food) .
  • the pill, tablet, capsule, or powder can be coated with a substance capable of protecting the composition from the gastric acid in the patient's stomach for a period of time sufficient to allow the composition to pass undisintegrated into the patient's small intestine.
  • the polymer may be administered alone or in combination with a pharmaceutically acceptable carrier substance, e.g. , magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.
  • a pharmaceutically acceptable carrier substance e.g. , magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.
  • the _in vitro potassium ion removal capabilities of various polymers were evaluated and (in some cases) compared to Kayexalate® and crosslinked polyacrylamide (prepared as described above) as follows. To a 40 mL centrifuge tube was added 0.50 g of poly
  • the mixture was shaken vigorously to disperse the polymer and then stirred at room temperature for two hours, after which it was centrifuged and decanted. The supernatant liquid was decanted and discarded. The wet, swollen polymer was then scraped out of the tube, weighed, vacuum dried, and weighed again. The dry polymer was sent to Schwartzkopf Laboratories for sodium and potassium analysis. The results are shown in Table 1 under the heading "centrifuged, unwashed samples.” All values are normalized per gram of polymer.
  • the percentage crosslinked refers to the weight percentage of crosslinking co-monomer (MBA or EBA) added.

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Abstract

Procédé permettant d'ajuster par échange ionique la concentration de certains ions chez un patient, consistant à administrer au patient une quantité thérapeutiquement efficace d'un ou plusieurs polymères réticulés qui sont atoxiques et stables après ingestion. Ces polymères ne provoquent pas de constipation et ne contiennent pas de particules abrasives, afin de réduire au minimum les risques d'irritation du tractus gastro-intestinal.
PCT/US1994/004538 1993-05-20 1994-04-25 Procede permettant d'ajuster la concentration ionique chez un patient et composition a cet effet Ceased WO1994027619A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68188/94A AU6818894A (en) 1993-05-20 1994-04-25 Process for adjusting ion concentration in a patient and compositions therefor

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US6511393A 1993-05-20 1993-05-20
US08/065,113 1993-05-20

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WO2007041569A1 (fr) 2005-09-30 2007-04-12 Ilypsa, Inc. Methodes et compositions permettant d'eliminer selectivement des ions potassium du tube digestif d'un mammifere
WO2007038801A3 (fr) * 2005-09-30 2007-11-08 Ilypsa Inc Compositions de liaison aux cations monovalents comprenant des particules coeur-ecorce avec des ecorces polyvinyliques reticulees et procedes pour les utiliser
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US8337824B2 (en) 2008-08-22 2012-12-25 Relypsa, Inc. Linear polyol stabilized polyfluoroacrylate compositions
US8586097B2 (en) 2005-09-30 2013-11-19 Relypsa, Inc. Methods for preparing core-shell composites having cross-linked shells and core-shell composites resulting therefrom
US9492476B2 (en) 2012-10-08 2016-11-15 Relypsa, Inc. Potassium-binding agents for treating hypertension and hyperkalemia

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US7385012B2 (en) 2003-11-03 2008-06-10 Ilypsa, Inc. Polyamine polymers
US7589238B2 (en) 2003-11-03 2009-09-15 Ilypsa, Inc. Treatment of hyperphosphatemia using crosslinked small molecule amine polymers
US7342083B2 (en) 2003-11-03 2008-03-11 Ilypsa, Inc. Polyamine polymers
US7459502B2 (en) 2003-11-03 2008-12-02 Ilypsa, Inc. Pharmaceutical compositions comprising crosslinked polyamine polymers
US7767768B2 (en) 2003-11-03 2010-08-03 Ilypsa, Inc. Crosslinked amine polymers
US7718746B2 (en) 2003-11-03 2010-05-18 Ilypsa, Inc. Anion-binding polymers and uses thereof
US7608674B2 (en) 2003-11-03 2009-10-27 Ilypsa, Inc. Pharmaceutical compositions comprising cross-linked small molecule amine polymers
US7335795B2 (en) 2004-03-22 2008-02-26 Ilypsa, Inc. Crosslinked amine polymers
US8349305B2 (en) 2004-03-22 2013-01-08 Ilypsa, Inc. Crosslinked amine polymers
US7754199B2 (en) 2004-03-22 2010-07-13 Ilypsa, Inc. Pharmaceutical compositions comprising crosslinked amine polymer with repeat units derived from polymerization of tertiary amines
USRE41316E1 (en) 2004-03-22 2010-05-04 Han Ting Chang Crosslinked amine polymers
EP2269590A3 (fr) * 2004-03-30 2011-10-05 Relypsa, Inc. Polymères se liant à des ions et leurs utilisations
AU2012254879B2 (en) * 2004-03-30 2016-05-19 Vifor Pharma Technology Ltd. Ion binding polymers and uses thereof
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US7556799B2 (en) 2004-03-30 2009-07-07 Relypsa, Inc. Ion binding polymers and uses thereof
US7488495B2 (en) 2004-03-30 2009-02-10 Relypsa, Inc. Ion binding polymers and uses thereof
US7776319B2 (en) 2004-03-30 2010-08-17 Relypsa, Inc. Methods and compositions for treatment of ion imbalances
US10485821B2 (en) 2004-03-30 2019-11-26 Vifor (International) Ltd. Ion binding polymers and uses thereof
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US8147873B2 (en) 2004-03-30 2012-04-03 Relypsa, Inc. Methods and compositions for treatment of ion imbalances
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US8586097B2 (en) 2005-09-30 2013-11-19 Relypsa, Inc. Methods for preparing core-shell composites having cross-linked shells and core-shell composites resulting therefrom
US9301974B2 (en) 2005-09-30 2016-04-05 Relypsa, Inc. Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal
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US10905711B2 (en) 2005-09-30 2021-02-02 Vifor (International) Ltd. Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal
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US10058567B2 (en) 2005-09-30 2018-08-28 Relypsa, Inc. Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal
US8337824B2 (en) 2008-08-22 2012-12-25 Relypsa, Inc. Linear polyol stabilized polyfluoroacrylate compositions
US9925212B2 (en) 2012-10-08 2018-03-27 Relypsa, Inc. Potassium-binding agents for treating hypertension and hyperkalemia
US10813946B2 (en) 2012-10-08 2020-10-27 Vifor (International) Ltd. Potassium binding polymers for treating hypertension and hyperkalemia
US9492476B2 (en) 2012-10-08 2016-11-15 Relypsa, Inc. Potassium-binding agents for treating hypertension and hyperkalemia
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