WO1994027620A1 - Composition et procede destines a eliminer les sels biliaires - Google Patents
Composition et procede destines a eliminer les sels biliaires Download PDFInfo
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- WO1994027620A1 WO1994027620A1 PCT/US1994/006042 US9406042W WO9427620A1 WO 1994027620 A1 WO1994027620 A1 WO 1994027620A1 US 9406042 W US9406042 W US 9406042W WO 9427620 A1 WO9427620 A1 WO 9427620A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
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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
- A61K31/795—Polymers containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
Definitions
- This invention relates to removing bile salts from a patient.
- Sequestering and removing bile salts in a patient can be used to reduce the patient's cholesterol level.
- Ion exchange resins which, when ingested, remove bile salts via the digestive tract, have been used for this purpose. Removal of bile salts will cause the body to prepare more bile salts. Because the biological precursor to bile salt is cholesterol, the metabolism of cholesterol to make bile salts is accompanied by a simultaneous reduction in the cholesterol in the patient.
- the invention features a method of removing bile salts from a patient by ion exchange that includes administering to the patient a therapeutically effective amount of one or more highly crosslinked polymers that are non-toxic and stable once ingested.
- the polymers are characterized by a repeat unit having the formula
- n is an integer
- R 1 is H or a c i"" 8 all ⁇ yl group (which may be straight chain or branched. O substituted or unsubstituted, e.g., methyl)
- M is -C-Z-R 2 or -Z-R 2
- Z is O, NR 3 , S, or (CH 2 ) m
- m 0-10
- R 3 is H or a C J -C 8 alkyl group (which may be straight chain or branched, substituted or unsubstituted, e.g., methyl); and
- R 2 is
- each R 4 , R 5 , and R 6 independently, is H, a CJL-C Q alkyl group (which may be straight chain or branched, substituted or unsubstituted, e.g. , methyl) , or an aryl group (e.g., having one or more rings and which may be substituted or unsubstituted, e.g., phenyl, naphthyl, imidazolyl, or pyridyl) .
- non-toxic it is meant that when ingested in therapeutically effective amounts neither the polymers nor any ions released into the body upon ion exchange are harmful.
- the ions released into the body are actually beneficial to the patient.
- the exchangeable ions are natural nutrients such as amino acids.
- 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 polymer is crosslinked by means of a multifunctional crosslinking co-monomer, the co-monomer being present in an amount from about 1-25% (more preferably about 2.5-20%) by weight, based upon total monomer weight.
- the polymer further preferably includes one or more hydrophobic co-monomers, e.g., styrene, vinyl naphthalene, ethyl vinylbenzene, N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, alkyl and aryl acrylates, alkyl and aryl methacrylates, and fluorinated derivatives of any of these co-monomers (e.g., p-fluorostyrene, pentafluorostyrene, hexafluoroisopropylacrylate, hexafluorobutylmethacrylate, or heptadecafluorodecylmethacrylate) .
- the alkyl groups are preferably C 1 -C 15 alkyl groups, and may be straight chain, branched, or cyclic (e.g., cyclohexyl) , and may further be substituted or unsubstituted.
- the aryl groups preferably have one or more rings and may be substituted or unsubstituted, e.g., phenyl, naphthyl, imidazolyl, or pyridyl.
- the polymer may also include one or more positively charged co-monomers, e.g., vinyl pyridine, dimethylaminomethyl styrene, or vinyl imidazole.
- the polymer may further include, as a co-monomer, one or more of the following: n- butyl ethacrylamide, hexafluorobutylmethacrylate, heptadecafluorodecylmethacrylate, styrene or fluorinated derivatives thereof, 2-vinyl naphthalene, 4-vinyl imidazole, vinyl pyridine, trimethylammoniumethylmethacrylate, or trimethylammoniumethylacrylate.
- a second example of a preferred polymer is characterized by a repeat unit having the formula
- the polymer may also include, as a co-monomer, one or more of the following: isopropylacrylamide, styrene or fluorinated derivatives thereof, hexafluoroisopropylacrylate, and trimethylammoniumethyl ethacry1ate.
- the polymer may also include, as a co-monomer, styrene or a fluorinated derivative thereof.
- a fourth example of a preferred polymer is characterized by a repeat unit having the formula
- a fifth example of a preferred polymer is characterized by a repeat unit having the formula
- a sixth example of a preferred polymer is characterized by a repeat unit having the formula
- the polymer may further include, as a co-monomer, ethyl vinylbenzene.
- a seventh example of a preferred polymer is characterized by a repeat unit having the formula
- the polymers may have fixed positive charges, or may have the capability of becoming charged upon ingestion at physiological pH. In the latter case, the charged ions also pick up negatively charged counterions upon ingestion that can be exchanged with bile salts. In the case of polymers having fixed positive charges, however, the polymer may be provided with one or more exchangeable counterions.
- suitable counterions include CI " , Br ⁇ , CH 3 OS0 3 " , HS0 4 " , S0 4 2" , HC0 3 ⁇ , C0 3 ", acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid.
- the 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 the bile salts being removed. More than one polymer, each having different counterions associated with the fixed charges, may be administered as well.
- the invention also features therapeutic compositions for removing bile salts that include a therapeutically effective amount of one or more of the above-described polymers.
- the invention features a highly crosslinked polymer composition that includes a polymer characterized by a repeat unit having the formula
- R 1 is H or methyl
- Q is -NH-(CH 2 ) 3 - or -0-(CH 2 ) 2 and n is an integer, and at least one additional co-monomer selected from the group consisting essentially of vinylnaphthalene, vinylimidazole, fluorinated derivatives of styrene, and fluorinated alkyl methacrylates.
- R 1 is methyl and Q is -NH-(CH 2 ) 3 -.
- This polymer may further comprise, as a co-monomer, trimethylammoniumethylacrylate or trimethylammoniumethylmethacrylate.
- Q is -0-(CH 2 ) .
- fluorinated styrene derivatives examples include p-fluorostyrene and pentafluorostyrene.
- suitable fluorinated alkyl methacrylates include hexafluorobutyl methacrylate and heptadecafluorodecyl methacrylate.
- the invention features a highly crosslinked polymer composition that includes a polymer characterized by a repeat unit having the formula
- R 1 is H or methyl
- Q is -NH-(CH 2 ) 3 - or -0-(CH 2 ) 2 and n is an integer, and, as additional co-monomers, (a) styrene and (b) trimethylammoniumethylacrylate or trimethylam oniumethylmethacrylate when R 1 is methyl and Q is -NH-(CH 2 ) 3 -, and methylacrylamidopropyltrimethylammonium when R 1 is H or methyl and Q is -0-(CH 2 ) .
- the invention features a method of synthesizing a highly crosslinked polymer having hydrophilic and hydrophobic units that includes reacting hydrophilic and hydrophobic monomers in the presence of an alcoholic solvent.
- the invention provides an effective treatment for removing bile salts from a patient (and thereby reducing the patient's cholesterol level) .
- 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 (when measured relative to gels such as cholestyramine) such that irritation to the gastrointestinal tract upon ingestion is minimized.
- the invention further provides an effective synthesis for polymers having hydrophilic and hydrophobic units by conducting the reaction in the presence of an alcoholic solvent not normally considered a good polymerization solvent due to its chain transfer properties.
- Preferred polymers have the formulae set forth in the Summary of the Invention, above.
- the polymers are highly crosslinked.
- the high level of crosslinking makes the polymers completely insoluble and thus limits their activity to the gastrointestinal tract only.
- the polymers are non-systemic in their activity and will lead to reduced side-effects in the patient.
- the polymers are preferably crosslinked 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, ethylenebismethacryla ide, ethylidene bisacrylamide, divinyl benzene, bisphenol A dimethacrylate, and bisphenol A diacrylate.
- diacrylates and dimethacrylates e.g., ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimeth
- crosslinking monomers are either commercially available or are prepared as described in Mandeville et al., "Process for Adjusting Ion Concentration in a Patient and Compositions Therefor," U.S.S.N. 08/065,113, filed May 20, 1993, assigned to the same assignee as the present application and hereby incorporated by reference.
- the amount of crosslinking co-monomer is typically between 1.0 and 25 weight %, based upon combined weight of crosslinking co- monomer and monomer, with 2.5-20% being preferred.
- the polymer includes one or more co- monomers that increase the overall hydrophobicity of the polymer.
- hydrophobic co-monomers aids in maximizing the selectivity of the interaction of the polymer with the bile salts.
- suitable hydrophobic co-monomers include, e.g., acrylamide, methacrylamide, and N-alkyl (e.g., methyl, ethyl, isopropyl, butyl, hexyl, dodecyl, cyclohexyl, dicyclohexyl) and N-aryl (e.g., phenyl, diphenyl) derivatives thereof; alkyl and aryl acrylates and methacrylates (e.g., ethyl, propyl, butyl, dodecyl), and fluorinated derivatives thereof (e.g., hexafluoroisopropyl acrylate, hexafluorobutyl " methacrylate, heptadecafluorodecyl
- the level of hydrophobicity needed may also be achieved simply by appropriate choice of crosslinking co- monomer.
- divinylbenzene is a suitable crosslinking co-monomer and is hydrophobic as well.
- the main "impurity" in divinylbenzene is ethylvinylbenzene, a hydrophobic, polymerizable monomer which will also contribute to the overall hydrophobicity of the polymer.
- Other hydrophobic crosslinking co- monomers include bisphenol A diacrylate and bisphenol A dimethacrylate. Examples A. Polymer Preparation
- methacrylamidopropyltrimethylammonium chloride (MAPTAC) (40 mL of a 50% aqueous solution, 21 g) , ethylene glycol dimethacrylate crosslinking co-monomer (5.00 g, 4.76 mL) , ethyl acetate (200 mL) , and 2-propanol (200 mL) .
- MTAC methacrylamidopropyltrimethylammonium chloride
- AIBN 0.1 g
- the solution was degassed with nitrogen for 5 minutes, at which point it turned cloudy, indicating that polymerization was proceeding.
- the reaction was maintained at 65°C for another 3 hours and then allowed to cool to room temperature.
- the resulting polymer (which was hard and sticky) was combined with 500 mL of water to soften it, and then transferred to a blender where it was blended with 1500 mL of 2-propanol and centrifuged. The mixture was then decanted and transferred to another blender with the aid of 100 mL of water. 800 mL of 2-propanol was then added and the mixture was blended, allowed to settle, and decanted.
- PolyMAPTAC crosslinked with 0.5% methylenebismethacrylamide crosslinking co-monomer; polyMAP AC crosslinked with 10% methylenebismethacrylamide crosslinking co-monomer; and polyMAPTAC crosslinked with 10% divinylbenzene crosslinking co-monomer were prepared in analogous fashion.
- the first step involved the preparation of ethylidenebisacetamide.
- Acetamide (118 g) , acetaldehyde (44.06 g) , copper acetate (0.2 g) , and water (300 L) were placed in a 1 L three neck flask fitted with condenser, thermometer, and mechanical stirrer.
- Concentrated HCI (34 L) was added and the mixture was heated to 45-50°C with stirring for 24 h.
- the water was then removed in vacuo to leave a thick sludge which formed crystals on cooling to 5°C.
- Acetone (200 L) was added and stirred for a few minutes, after which the solid was filtered off and discarded.
- the acetone was cooled to 0°C and solid was filtered off. This solid was rinsed in 500 mL acetone and air dried 18 h to yield 31.5 g of ethylidenebisacetamide.
- the next step involved the preparation of vinylacetamide from ethylidenebisacetamide.
- Ethylidenebisacetamide (31.05 g) , calcium carbonate (2 g) and celite 541 (2 g) were placed in a 500 mL three neck flask fitted with a thermometer, a mechanical stirrer, and a distilling head atop a Vigroux column.
- the mixture was vacuum distilled at 35 mm Hg by heating the pot to 180-225°C. Only a single fraction was collected (10.8 g) which contained a large portion of acetamide in addition to the product (determined by NMR) .
- This solid product was dissolved in isopropanol (30 mL) to form the crude vinylacetamide solution used for polymerization.
- Poly(vinylacetamide) (0.79 g) was placed in a 100 L one neck flask containing water (25 mL) and cone. HCI (25 mL) . The mixture was refluxed for 5 days, after which the solid was filtered off, rinsed once in water, twice in isopropanol, and dried in a vacuum oven to yield 0.77 g of product. Infrared spectroscopy indicated that a significant amount of the amide (1656 cm" 1 ) remained and that not much amine (1606 cm” 1 ) was formed. The product of this reaction (-0.84 g) was suspended in NaOH (46 g) and water (46 g) and heated to boiling ( ⁇ 140°C) .
- Dimethylaminopropylacryla ide (10 g) and methylenebisacrylamide crosslinking co-monomer (1.1 g) were dissolved in 50 mL of water in a 100 mL three neck flask. The solution was stirred under nitrogen for 10 minutes. Potassium persulfate (0.3 g) and sodium metabisulfite (0.3 g) were each dissolved in 2-3 mL of water and then mixed. After a few seconds this solution was added to the monomer solution, still under nitrogen. A gel formed immediately and was allowed to sit overnight. The gel was removed and blended with 500 mL of isopropanol. The solid was filtered off and rinsed three times with acetone. The solid white powder was filtered off and dried in a vacuum oven to yield 6.1 g.
- Dimethylaminopropylmethacrylamide (20.0 g) was dissolved in water (100 L) and neutralized with concentrated HCI to pH 6.94.
- Methylenebisacrylamide crosslinking co-monomer (2.2 g) was added and the solution was warmed (39°C) to dissolve.
- Potassium persulfate (0.3 g) and potassium metabisulfite (0.3 g) were added with stirring under a nitrogen atmosphere. After gellation, the solution was allowed to sit overnight, blended with isopropanol (500 L) twice, and dried in a vacuum oven to yield 27.65 g of product.
- the co-monomer n-butylmethacrylamide (BuMA) was prepared as follows. Methacryloyl chloride (48.4mL, 52.3g, 0.500mol) was dissolved in tetrahydrofuran (300 mL) in a 1 L flask and placed in an ice bath. A solution containing butylamine (36.6 g) and triethylamine (55.6 g) was added dropwise, maintaining the temperature at 5-15°C. After addition the solution was stirred for 5 min and the solid triethylamine hydrochloride was filtered off and discarded. The solvent was removed in vacuo from the mother liquor and the resulting yellow oil was used without further purification. The yield was 71.58g of BuMA co-monomer.
- methacrylamidopropyltrimethylammoniu chloride (MAPTAC) (108 mL of a 50% aqueous solution, 56.8 g) , ethylene glycol dimethacrylate crosslinking co-monomer (19.62 g) , BuMA co-monomer (12.12g), and 2-propanol (850 mL) .
- MATAC methacrylamidopropyltrimethylammoniu chloride
- ethylene glycol dimethacrylate crosslinking co-monomer (19.62 g)
- BuMA co-monomer (12.12g)
- 2-propanol 850 mL
- the catalyst consisting of a solution of potassium persulfate (0.75g) and potassium metabisulfate (0.75g) in 25mL of water was added.
- the solution immediately began to turn cloudy, indicating that polymerization was proceeding.
- the reaction was maintained at 40°C for 24 hours and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and vacuum dried to afford 64.54 g of the title polymer.
- Polymer for testing was washed two times with 800mL of water each time, followed by two washes with 500 mL of methanol each time to give 34.5 g of purified polymer.
- a crosslinked MAPTAC co-BuMA copolymer was also prepared using propylene glycol dimethacrylate, rather than ethylene glycol dimethacrylate, as the crosslinking co-monomer, as follows.
- methacrylamidopropyltrimethylammonium chloride (MAPTAC) (60 mL of a 50% aqueous solution, 31.5 g) , propylene glycol dimethacrylate crosslinking co-monomer (9.81 g) , BuMA co-monomer (6.06g), and 2-propanol (300 mL) .
- MTAC methacrylamidopropyltrimethylammonium chloride
- MAPTAC coBuMA (5%) crosslinked with 24% ethyleneglycoldimethacrylate crosslinking co-monomer, MAPTAC coBuMA (2)%) crosslinked with 0.5% methylenebismethacrylamide crosslinking co-monomer, and MAPTAC coBuMA (14%) crosslinked with 22% propyleneglycoldimethacrylate crosslinking co-monomer were prepared in analogous fashion by adjusting the ratios of starting monomers. 7.
- methacrylamidopropyltrimethyl-ammonium chloride (MAPTAC) (60 mL of a 50% aqueous solution, 31.5 g) , divinyl benzene crosslinking co-monomer (2.00 g) , styrene co- monomer (1.75g), and 2-propanol (300 mL) .
- the resulting solution was clear.
- the reaction mixture was heated to 60°C while being degassed with nitrogen. When the solution had reached 60°C, the catalyst, AIBN (0.50g), was added. The solution immediately began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 60°C for 24 hours and then allowed to cool to room temperature.
- methacrylamidopropyltrimethylammonium chloride (MAPTAC) (40 mL of a 50% aqueous solution, 21.0 g) , divinyl benzene crosslinking co-monomer (2.25 g) , 2- vinylnaphthalene co-monomer (10.5 g) , and 2-propanol (320 mL) .
- the resulting solution was clear.
- the reaction mixture was heated to 65°C while being degassed with nitrogen. When the solution had reached 65°C, the catalyst, AIBN (0.50g), was added. The solution immediately began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 65°C for 20 hours and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and then immediately slurried in 400 mL of distilled water. The mixture was stirred for 1/2 hour and then filtered. The water wash was repeated one more time. The filter cake was then slurried in 400 mL of methanol and stirred for 1/2 hour. The mixture was filtered and the methanol slurry was repeated one more time. Vacuum drying afforded 22.11 g, 65.5% of the title polymer.
- MAPTAC co-VN (39%) crosslinked with 5% divinyl benzene crosslinking co-monomer was prepared in analogous fashion by varying the ratio of starting monomers.
- the resulting polymer was filtered and washed on the funnel with isopropanol, and then immediately slurried in 500 mL of distilled water. The mixture was stirred for 1/2 hour and then filtered. The water wash was repeated one more time. The filter cake was then slurried in 400 L of methanol and stirred for 1/2 hour. The mixture was filtered and the methanol slurry was repeated one more time. Vacuum drying afforded 7.34 g, 20.5% of the title polymer.
- TMAEAC trimethylammoniumethylacrylatechloride
- the resulting polymer was filtered and washed on the funnel with isopropanol, and then immediately slurried in 1000 mL of distilled water. The mixture was stirred for 1/2 hour and then 800 mL of methanol was added and the mixture was stirred for an additional 1/2 hour. The mixture was allowed to settle and the supernatant liquid was decanted, leaving a residue of about 750 mL. The residue was then slurried with an additional 750 mL of methanol and stirred for 1/2 hour. The methanol slurry and decantation process was repeated two more times with 800 mL of methanol each time. Next, 800 mL of isopropanol was added and the mixture was stirred for 1/2 hour and then filtered.
- TMAEAC co-Sty (31%) crosslinked with 8% divinylbenzene crosslinking co-monomer and TMAEAC co-Sty (46%) crosslinked with 6% divinylbenzene crosslinking co- monomer were prepared in analogous fashion by varying the ratio of starting monomers. 11.
- TMAEMC co-Stv Poly(trimethy1ammoniumethylmethacry1ate- chloride co-polv(styrene)
- TMAEMAC trimethylammoniumethylmethacrylatechloride
- TMAEMC co-Sty (58%) crosslinked with 4% divinylbenzene crosslinking co-monomer
- TMAEMC co-Sty (33%) crosslinked with 4% divinylbenzene crosslinking co- monomer
- TMAEMC co-Sty (24%) crosslinked with 4% divinylbenzene crosslinking co-monomer were prepared in analogous fashion by varying the ratio of starting monomers.
- reaction mixture was heated to 65°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding. After five hours the mixture was very thick so an additional 100 mL of isopropanol was added. The reaction was maintained at 65°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 mL of distilled water. The mixture was stirred for 1/2 hour. The polymer slurry was filtered and 500 mL of distilled water was added and the mixture was stirred for 1/2 hour. The mixture was filtered and the filter cake was slurried two times in 300 mL of methanol each time. Filtration and air drying afforded 7.74 g of the title co-polymer.
- MAPTAC co-StyF 5 (20%) crosslinked with 5% divinylbenzene crosslinking co-monomer
- MAPTAC co-StyF 5 40%) crosslinked with 5% divinylbenzene crosslinking co- monomer
- MAPTAC co-StyF 5 45% crosslinked with 5% divinylbenzene crosslinking co-monomer were prepared in analogous fashion by varying the ratio of starting monomers.
- reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 mL of methanol. The mixture was stirred for 1/2 hour. The polymer slurry was filtered and 400 mL of distilled water was added and the mixture was stirred for 1/2 hour. The mixture was filtered and the water slurry was repeated. The mixture was filtered and the filter cake was slurried two times in 400 mL of methanol each time. Filtration and air drying afforded 5.39 g of the title co-polymer.
- MAPTAC co-TMAEMC (34%) co-Sty (36%) crosslinked with 5% divinylbenzene crosslinking co-monomer
- MAPTAC co-TMAEMC (31%) co-Sty (41%) crosslinked with 5% divinylbenzene crosslinking co-monomer
- MAPTAC co-TMAEMC 28%) co-Sty (46%) crosslinked with 5% divinylbenzene crosslinking co-monomer
- MAPTAC co-TMAEMC (23%) co-Sty (48%) crosslinked with 5% divinylbenzene crosslinking co- monomer
- MAPTAC co-TMAEMC (26%) co-Sty (52%) crosslinked with 4% divinylbenzene crosslinking co-monomer
- MAPTAC co-TMAEMC (17%) co-Sty (53%) crosslinked with 4% divinylbenzene crosslinking co-monomer
- MAPTAC co-TMAEMC (15%) co-Sty (55
- the co-monomer isopropylacrylamide (IPA) was first prepared as follows.
- the gel was transferred to a blender and 1000 mL of water was added. After blending for a few seconds, the polymer had swelled to take up all of the water. The swollen polymer was blended in several portions with isopropanol several times to dehydrate it. The resulting polymer was filtered and washed on the funnel with isopropanol and vacuum dried to afford 36.8 g of the title co-polymer.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 1000 mL of distilled water. The mixture was stirred for 1 hour. The polymer slurry was filtered, washed on the funnel with methanol, and then slurried in 600 mL of methanol for one hour. Filtration and air drying afforded 20.4 g of co-polymer.
- TMAEMC trimethylammoniumethylmethacrylate chloride
- TMAEMC co-F ⁇ ty (24%) crosslinked with 4% divinylbenzene crosslinking co-monomer was prepared in analogous fashion by varying the ratio of the starting monomers.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 mL of distilled water. The mixture was stirred for 1 hour. The polymer slurry was filtered and the water slurry was repeated one more time. The polymer was then slurried in 500 mL of methanol for one hour and filtered.
- the residual polymer was slurried in 400 L of water, stirred for one hour and filtered. The water slurry was repeated one more time. Next the polymer was slurried two times in methanol. Finally, the polymer was slurried in 200 mL of isopropanol, stirred for two hours and filtered. Air drying afforded 5.59 g of the title polymer.
- reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding.
- the reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 mL of methanol. The mixture was stirred for 1/2 hour .
- the polymer slurry was allowed to settle and decanted.
- MAPTAC co-TMAEAC (10%) co-Sty (60%) crosslinked with 5% divinylbenzene crosslinking co-monomer was prepared in analogous fashion by varying the ratio of starting monomers.
- TMAEAC 2-(trimethylammonium) ethyl acrylate chloride
- TMAEAC co-StyF 5 (20%) crosslinked with 5% divinylbenzene crosslinking co-monomer was prepared in analogous fashion by varying the ratio of starting monomers.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 L of distilled water. The mixture was stirred for 1/4 hour. The polymer slurry was filtered and 500 mL of distilled water was added and the mixture was stirred for 1/4 hour. The water slurry was repeated one more time. The mixture was filtered and the filter cake was slurried three times in 300 mL of methanol each time. Filtration and air drying afforded 1.26 g of the title co-polymer.
- TMAEMC co-StyF 5 (24%) crosslinked with 4% divinylbenzene crosslinking co-monomer
- TMAEMC co- StyF 5 (39%) crosslinked with 4% divinylbenzene crosslinking co-monomer were prepared in analogous fashion by varying the ratio of starting monomers.
- reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 500 mL of methanol. The mixture was stirred for 1/4 hour. The polymer slurry was filtered and then slurried 3 times in 300 mL of water each time. The last time the polymer slurry was blended for 5 minutes. The mixture was filtered and the filter cake was slurried two times in
- TMAEAC 2-(trimethylammonium) ethyl acrylate chloride
- TMAEMC 2-(trimethylammonium) ethyl methacrylate chloride
- divinylbenzene crosslinking co-monomer (1.00 g)
- styrene 13.00 g
- 2-propanol 150 mL
- AIBN AIBN
- reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding.
- the reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was filtered and washed on the funnel with isopropanol and immediately slurried in 400 mL of methanol. The mixture was stirred for 1/2 hour.
- the polymer slurry was filtered and then slurried 2 times in 250 mL of water each time. The last time the polymer slurry was blended for 5 minutes.
- the mixture was filtered and the filter cake was slurried two times in 250 mL of methanol each time. Filtration and vacuum drying afforded 7.80 g of co-polymer.
- TMAEAC trimethylammonium ethylmethacrylate chloride
- TMAEMC co-2,3,4,5,6-pentafluorostyrene
- TMAEAC 2-(trimethylammonium) ethyl acrylate chloride
- TMAEMC 2-(trimethylammonium) ethyl methacrylate chloride
- divinylbenzene crosslinking co-monomer (1.00 g)
- pentafluorostyrene 13.00 g
- 2-propanol 150 mL
- AIBN 0.50g
- reaction mixture was heated to 70°C while being degassed with nitrogen. After a short period of time, the solution began to turn cloudy, indicating that polymerization was proceeding. The reaction was maintained at 70°C for 24 hours, and then allowed to cool to room temperature.
- the resulting polymer was decanted and immediately slurried in 400 mL of methanol. The mixture was stirred for 1/2 hour. The polymer slurry was filtered and then slurried two times in 200 mL of water each time. The second time the polymer slurry was blended for 5 minutes. The mixture was filtered and the filter cake was slurried two times in 200 mL of methanol each time. Vacuum drying afforded 6.87 g of co-polymer. Testing of Polymers A. Preparation of Artificial Intestinal Fluid
- Sodium carbonate (1.27g) and sodium chloride (1.87g) were dissolved in 400 mL of distilled water.
- a mixture of purified bile acids consisting of taurocholic acid (0.138g, 0.24mmol), glycocholic acid (0.292g, 0.60mmol), glycodeoxycholic acid (0.085mmol, O.l ⁇ mmol) and glycochenodeoxycholic acid (0.085mmol, 0.18mmol).
- the pH of the solution was adjusted to 7.20 with acetic acid. This solution was used for the testing of the various polymers.
- the total bile salt concentration in this solution is 3 millimolar, a concentration approximately equal to that found in normal physiological solutions in the duodenum. Polymers were tested as follows.
- NAD+ solution containing 7mM NAD+ at pH 7.0.
- HSD solution containing 2units/mL in Tris-HCl buffer (0.03M Tris, ImM EDTA) at pH 7.2.
- 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 bile salt 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.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7500999A JPH09500368A (ja) | 1993-06-02 | 1994-05-27 | 胆汁酸塩を除去するための組成物および方法 |
AU70479/94A AU7047994A (en) | 1993-06-02 | 1994-05-27 | Compositions and process for removing bile salts |
EP94919283A EP0706399A4 (fr) | 1993-06-02 | 1994-05-27 | Composition et procede destines a eliminer les sels biliaires |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7156493A | 1993-06-02 | 1993-06-02 | |
US08/071,564 | 1993-06-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994027620A1 true WO1994027620A1 (fr) | 1994-12-08 |
Family
ID=22102137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/006042 WO1994027620A1 (fr) | 1993-06-02 | 1994-05-27 | Composition et procede destines a eliminer les sels biliaires |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0706399A4 (fr) |
JP (1) | JPH09500368A (fr) |
AU (1) | AU7047994A (fr) |
WO (1) | WO1994027620A1 (fr) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995034588A1 (fr) * | 1994-06-10 | 1995-12-21 | Geltex Pharmaceuticals, Inc. | Polymeres reticules utilises pour eliminer les sels biliaires d'un patient |
WO1996039449A1 (fr) * | 1995-06-06 | 1996-12-12 | Geltex Pharmaceuticals, Inc. | Agent sequestrant hydrophobe contenant des heteroatomes et permettant une depletion cholesterolique |
US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US5679717A (en) * | 1994-06-10 | 1997-10-21 | Geltex Pharmaceuticals, Inc. | Method for removing bile salts from a patient with alkylated amine polymers |
US5702696A (en) * | 1993-05-20 | 1997-12-30 | Geltex Pharmaceuticals | Iron-binding polymers for oral administration |
FR2757866A1 (fr) * | 1996-12-30 | 1998-07-03 | Catalyse | Polymeres comportant des groupes ammoniums quaternaires, leur utilisation pour la fabrication d'un materiau a propretes antibacteriennes et leurs procedes de preparation |
WO1998043653A1 (fr) * | 1997-03-27 | 1998-10-08 | Geltex Pharmaceuticals, Inc. | Reseaux de polymeres enchevetres servant a la sequestration d'acides biliaires |
US5840766A (en) * | 1993-06-02 | 1998-11-24 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5900475A (en) * | 1994-06-10 | 1999-05-04 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
US5929184A (en) * | 1993-06-02 | 1999-07-27 | Geltex Pharmaceuticals, Inc. | Hydrophilic nonamine-containing and amine-containing copolymers and their use as bile acid sequestrants |
US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
WO2000064428A2 (fr) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Agent sequestrant les acides biliaires a base de polyether |
US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
EP1133989A2 (fr) * | 1993-08-11 | 2001-09-19 | Geltex Pharmaceuticals, Inc. | Polymère à utilisation thérapeutique |
US6423754B1 (en) | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
US6726905B1 (en) | 1997-11-05 | 2004-04-27 | Genzyme Corporation | Poly (diallylamines)-based phosphate binders |
AU774636B2 (en) * | 1999-07-14 | 2004-07-01 | Genzyme Corporation | Fat-binding polymers, optionally combined with lipase inhibitors |
US7014846B2 (en) | 1993-08-11 | 2006-03-21 | Genzyme Corporation | Phosphate-binding polymers for oral administration |
WO2012027331A1 (fr) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés |
US8187631B2 (en) | 1999-10-19 | 2012-05-29 | Genzyme Corporation | Direct compression polymer tablet core |
US8986669B2 (en) | 2005-09-02 | 2015-03-24 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
US9095509B2 (en) | 2005-09-15 | 2015-08-04 | Genzyme Corporation | Sachet formulation for amine polymers |
US9555056B2 (en) | 2004-11-01 | 2017-01-31 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
US11267924B2 (en) | 2014-12-18 | 2022-03-08 | Genzyme Corporation | Crosslinked polydiallymine copolymers for the treatment of type 2 diabetes |
Families Citing this family (4)
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WO2002085382A1 (fr) * | 2001-04-18 | 2002-10-31 | Genzyme Corporation | Methodes pour traiter le syndrome x avec des polyamines aliphatiques |
US20070212325A1 (en) | 2004-03-26 | 2007-09-13 | Mitsubishi Pharma Corporation | Insulin Resistance-Improving Agent |
DE102006007564A1 (de) * | 2006-02-16 | 2007-08-30 | Röhm Gmbh | Nanoskalige superparamagnetische Poly(meth)acrylatpolymere |
US20090162311A1 (en) | 2006-06-16 | 2009-06-25 | Masahiko Yamamori | Agent for Prevention and/or Treatment of Glomerulopathy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3953406A (en) * | 1973-01-26 | 1976-04-27 | California Institute Of Technology | Water-insoluble, swellable polyurethanes |
US4412011A (en) * | 1981-03-02 | 1983-10-25 | Mitsubishi Petrochemical Co., Ltd. | Polymeric cholesterol reducing agent having vinylimidazole pendant groups |
US4557930A (en) * | 1982-01-18 | 1985-12-10 | Mitsubishi Petrochemical Co., Ltd. | Anticholesteremic anion exchange resins |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3308020A (en) * | 1961-09-22 | 1967-03-07 | Merck & Co Inc | Compositions and method for binding bile acids in vivo including hypocholesteremics |
ES2006782A6 (es) * | 1987-07-15 | 1989-05-16 | Garcia Alonso Julio | Procedimiento de obrencion de resinas intercambiadoras anionicas de uso humano |
GB8829088D0 (en) * | 1988-12-13 | 1989-01-25 | Smith Kline French Lab | Compounds |
JPH059234A (ja) * | 1991-06-28 | 1993-01-19 | Chuichi Hirayama | 発熱物質吸着体 |
-
1994
- 1994-05-27 JP JP7500999A patent/JPH09500368A/ja active Pending
- 1994-05-27 EP EP94919283A patent/EP0706399A4/fr not_active Withdrawn
- 1994-05-27 WO PCT/US1994/006042 patent/WO1994027620A1/fr not_active Application Discontinuation
- 1994-05-27 AU AU70479/94A patent/AU7047994A/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3953406A (en) * | 1973-01-26 | 1976-04-27 | California Institute Of Technology | Water-insoluble, swellable polyurethanes |
US4412011A (en) * | 1981-03-02 | 1983-10-25 | Mitsubishi Petrochemical Co., Ltd. | Polymeric cholesterol reducing agent having vinylimidazole pendant groups |
US4557930A (en) * | 1982-01-18 | 1985-12-10 | Mitsubishi Petrochemical Co., Ltd. | Anticholesteremic anion exchange resins |
Non-Patent Citations (1)
Title |
---|
See also references of EP0706399A4 * |
Cited By (53)
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US6605270B1 (en) | 1993-05-20 | 2003-08-12 | Genzyme Corporation | Iron-binding polymers for oral administration |
US5702696A (en) * | 1993-05-20 | 1997-12-30 | Geltex Pharmaceuticals | Iron-binding polymers for oral administration |
US5840766A (en) * | 1993-06-02 | 1998-11-24 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5624963A (en) * | 1993-06-02 | 1997-04-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
US6060517A (en) * | 1993-06-02 | 2000-05-09 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5929184A (en) * | 1993-06-02 | 1999-07-27 | Geltex Pharmaceuticals, Inc. | Hydrophilic nonamine-containing and amine-containing copolymers and their use as bile acid sequestrants |
US7459151B2 (en) | 1993-08-11 | 2008-12-02 | Genzyme Corporation | Phosphate-binding polymers for oral administration |
US7014846B2 (en) | 1993-08-11 | 2006-03-21 | Genzyme Corporation | Phosphate-binding polymers for oral administration |
EP1133989A3 (fr) * | 1993-08-11 | 2004-05-12 | Genzyme Corporation | Polymère à utilisation thérapeutique |
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US7101960B2 (en) | 1994-06-10 | 2006-09-05 | Genzyme Corporation | Process for removing bile salts from a patient and alkylated compositions therefor |
US5693675A (en) * | 1994-06-10 | 1997-12-02 | Geltex Pharmaceuticals Inc. | Alkylated amine polymers |
US5900475A (en) * | 1994-06-10 | 1999-05-04 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
US5917007A (en) * | 1994-06-10 | 1999-06-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
US5919832A (en) * | 1994-06-10 | 1999-07-06 | Geltex Pharmaceuticals Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US7399821B2 (en) | 1994-06-10 | 2008-07-15 | Genzyme Corporation | Alkylated poly(allylamine) polymers and methods of use |
WO1995034588A1 (fr) * | 1994-06-10 | 1995-12-21 | Geltex Pharmaceuticals, Inc. | Polymeres reticules utilises pour eliminer les sels biliaires d'un patient |
US5969090A (en) * | 1994-06-10 | 1999-10-19 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
US5981693A (en) * | 1994-06-10 | 1999-11-09 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US6066678A (en) * | 1994-06-10 | 2000-05-23 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
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US5618530A (en) * | 1994-06-10 | 1997-04-08 | Geltex Pharmaceuticals, Inc. | Hydrophobic amine polymer sequestrant and method of cholesterol depletion |
US5679717A (en) * | 1994-06-10 | 1997-10-21 | Geltex Pharmaceuticals, Inc. | Method for removing bile salts from a patient with alkylated amine polymers |
US6433026B2 (en) | 1994-06-10 | 2002-08-13 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
US6225355B1 (en) | 1994-06-10 | 2001-05-01 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
WO1996039449A1 (fr) * | 1995-06-06 | 1996-12-12 | Geltex Pharmaceuticals, Inc. | Agent sequestrant hydrophobe contenant des heteroatomes et permettant une depletion cholesterolique |
AU706788B2 (en) * | 1995-06-06 | 1999-06-24 | Geltex Pharmaceuticals, Inc. | Hydrophobic heteroatom-containing sequestrant for cholesterol depletion |
WO1998029463A1 (fr) * | 1996-12-30 | 1998-07-09 | Catalyse | Polymeres antimicrobiens comportant des groupes ammonium quaternaire, leur utilisation pour la fabrication d'un materiau a proprietes antimicrobiennes et leurs procedes de preparation |
US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
US6610283B1 (en) | 1996-12-30 | 2003-08-26 | Genzyme Corporation | Poly(diallylamine)-based bile acid sequestrants |
US6251967B1 (en) | 1996-12-30 | 2001-06-26 | Catalyse (Sarl) Limited Company | Antimicrobial polymers comprising quaternary ammonium groups, their use for making a material with antimicrobial properties and methods for preparing them |
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FR2757866A1 (fr) * | 1996-12-30 | 1998-07-03 | Catalyse | Polymeres comportant des groupes ammoniums quaternaires, leur utilisation pour la fabrication d'un materiau a propretes antibacteriennes et leurs procedes de preparation |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
WO1998043653A1 (fr) * | 1997-03-27 | 1998-10-08 | Geltex Pharmaceuticals, Inc. | Reseaux de polymeres enchevetres servant a la sequestration d'acides biliaires |
US6423754B1 (en) | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
US6726905B1 (en) | 1997-11-05 | 2004-04-27 | Genzyme Corporation | Poly (diallylamines)-based phosphate binders |
WO2000064428A2 (fr) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Agent sequestrant les acides biliaires a base de polyether |
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US6517825B1 (en) | 1999-04-23 | 2003-02-11 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
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US9895315B2 (en) | 2004-11-01 | 2018-02-20 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
US8986669B2 (en) | 2005-09-02 | 2015-03-24 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
US9095509B2 (en) | 2005-09-15 | 2015-08-04 | Genzyme Corporation | Sachet formulation for amine polymers |
US9585911B2 (en) | 2005-09-15 | 2017-03-07 | Genzyme Corporation | Sachet formulation for amine polymers |
WO2012027331A1 (fr) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés |
US11267924B2 (en) | 2014-12-18 | 2022-03-08 | Genzyme Corporation | Crosslinked polydiallymine copolymers for the treatment of type 2 diabetes |
Also Published As
Publication number | Publication date |
---|---|
EP0706399A4 (fr) | 1998-08-12 |
JPH09500368A (ja) | 1997-01-14 |
EP0706399A1 (fr) | 1996-04-17 |
AU7047994A (en) | 1994-12-20 |
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