WO2002032974A2 - Polymere et son utilisation - Google Patents

Polymere et son utilisation Download PDF

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Publication number
WO2002032974A2
WO2002032974A2 PCT/JP2001/007958 JP0107958W WO0232974A2 WO 2002032974 A2 WO2002032974 A2 WO 2002032974A2 JP 0107958 W JP0107958 W JP 0107958W WO 0232974 A2 WO0232974 A2 WO 0232974A2
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WIPO (PCT)
Prior art keywords
group
salt
lower alkyl
polymer
polymerization
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PCT/JP2001/007958
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English (en)
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WO2002032974A3 (fr
Inventor
Akira Yamada
Norihiko Shimazaki
Osamu Nakayama
Miwako Shobo
Yoshimitsu Nakajima
Hideo Sawada
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from AUPR0850A external-priority patent/AUPR085000A0/en
Priority claimed from AUPR3754A external-priority patent/AUPR375401A0/en
Priority claimed from AUPR7382A external-priority patent/AUPR738201A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU2001286228A priority Critical patent/AU2001286228A1/en
Publication of WO2002032974A2 publication Critical patent/WO2002032974A2/fr
Publication of WO2002032974A3 publication Critical patent/WO2002032974A3/fr

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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
    • 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
    • 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
    • C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • 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
    • C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
    • C08F230/04—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal
    • C08F230/08—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon
    • C08F230/085—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon the monomer being a polymerisable silane, e.g. (meth)acryloyloxy trialkoxy silanes or vinyl trialkoxysilanes
    • 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
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C08F251/02—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof on to cellulose or derivatives thereof

Definitions

  • This invention relates to a kind of novel polymers having ability for adsorbing phosphate, to a pharmaceutical composition containing the same and to their use as a medicament.
  • Renal insufficient patients have difficulties in excretion of phosphate to urine.
  • Accumulated phosphate in the patient causes central and peripheral neuropathy, cardiomyopathy, hyperlipidemia, glycometabolism disorder, pruritus, anemia, hypogonadism, disorder for diffusing of the lung, arteriosclerosis, immunodeficiency, renal failure, etc. (Jin to Touseki, 31, 2: 3211994).
  • Even during dialysis those pathemas and complications cannot be dissolved. Therefore, it is essential for the renal insufficient patients to treat hyperphosphoremia.
  • dietotherapy and/ or administration of a peroral phosphate adsorbent are applied for treating hyperphosphoremia.
  • the dietotherapy is not effective for decreasing the amount of phosphate in the blood because it is inevitable for the patient to have some amount of proteins in the ingesta.
  • aluminum preparation e.g., aluminum hydroxide
  • calcium preparation e.g., calcium carbonate, calcium acetate
  • magnesium preparation e.g., magnesium carbonate
  • anion-exchange resins e.g., Rena Gel®, manufactured by Chugai Pharmaceutical Co., Ltd. and Kirin Brewery Company, Limited
  • anion-exchange resins e.g., Rena Gel®, manufactured by Chugai Pharmaceutical Co., Ltd. and Kirin Brewery Company, Limited
  • anion-exchange resins e.g., Rena Gel®, manufactured by Chugai Pharmaceutical Co., Ltd. and Kirin Brewery Company, Limited
  • the aluminum preparation, calcium preparation and magnesium preparation are adsorbed through the intestine and tend to accumulate in the body, and the anion- exchange resins tend to cause side effects such as constipation, diarrhea, flatus, nausea, emesis, etc.
  • the dose of the anion- exchange resins is so large due to low ability of adsorption that intensifies such side effects
  • an object of this invention is to provide a kind of novel polymers having ability for adsorbing phosphate. Since the polymer of the present invention has stronger ability of adsorption, the dosage of the polymer can be reduced.
  • Another object of this invention is to provide a pharmaceutical composition containing a polymer as an active ingredient. Further object of this invention is to provide a use of the polymers for treating or preventing hyperphosphoremia.
  • novel polymers of this, invention have ability for adsorbing phosphate and can be obtained by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25 in the presence of a radical initiator
  • R 1 and R 3 are each hydrogen atom or lower alkyl group
  • R 2 and R 4 are each acyl group, aliphatic silyl group, a ino lower alkyl group which may have one or more suitable substituent(s), heterocyclic group which may have one or more suitable substituent(s) or carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.
  • Examples of “one or more” are the numbers of 1 to 6, in which the preferred one is the number of 1 to 3, and the most preferred one is the number of 1 or 2.
  • halogen are fluorine, chlorine, bromine, iodine and the like.
  • lower alkoxy moiety include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pent loxy, neo-pentyloxy, hexyloxy, isohexyloxy or the like.
  • lower alkyl moiety include straight or branched ones having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert- pentyl, neo-pentyl, hexyl, isohexyl or the like.
  • aryl and “ar” moiety include phenyl which may have lower alkyl (e.g., phenyl, mesityl, xylyl or tolyl), naphthyl, anthryl, indanyl, fluorenyl or the like, and this "aryl” and “ar” moiety may have one or more halogen.
  • aroyl include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl and the like.
  • acyl group examples include aliphatic acyl, aromatic acyl, arylaliphatic aciyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid and sulfonic acid.
  • acyl group More preferred examples of the "acyl group" are illustrated as follows: carboxy; carbamoyl; mono or di(lower)alkylcarbamoyl (e.g., methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, n-butylcarbamoyl or 1,1- dimethylcarbamoyl); aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl,
  • heterocycliccarbonyl , “heterocyclicoxycarbonyl” , “heterocyclic(lower)alkanoyl”, “heterocyclic(lower)alkenoyl” and
  • heterocyclicglyoxyloyl can be referred to aforementioned “heterocyclic” moieties.
  • lower alkyl group for R 1 and R 3 are referred to aforementioned "lower alkyl", in which the more preferred ones are methyl, ethyl, propyl, n-butyl, t-butyl, pentyl and n-hexyl.
  • acyl group for R 2 and R 4 can be referred to aforementioned "acyl group", in which the more preferred ones are lower alkylcarbamoyl group such as methylcarbamoyl, dim.ethylcarbam.oyl, ethylcarbamoyl, propylcarbamoyl, n- butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and 1,1- dimethylethylcarbamoyl; aiylcarbamoyl group such as phenylcarbamoyl and naphthylcarbamoyl; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; aforementioned heterocyclicoxycarbonyl group, in which
  • Preferred examples of the aliphatic silyl group for R 2 and R 4 are tri ⁇ iethylsilyl and triethylsilyl.
  • Preferred examples of the amino (lower) alkyl group for R 2 and R 4 are aminomethyl, aminoethyl, aminopropyl, amino-n-butyl, aminopentyl and aminohexyl.
  • heterocyclic group for R 2 and R 4 can be referred to aforementioned "heterocyclic group", in which the more preferred ones are pyridyl, thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, isoxazolyl and quinolyl.
  • the above lower alkylcarbamoyl group, aiylcarbamoyl group, lower alkoxycarbonyl group, heterocyclicoxycarbonyl group, heterocycliccarbonyl group, amino (lower) alkyl group and heterocyclic group may have one or more substituent(s) selected from the group consisting of sulfo; hydroxy; carboxy; amino; sulfo (lower) al yl- cfi(lower)a-kylamino such as sulfopropyl-di-methylarnino, sulfomethyl- dimethylamino and sulfoethyl-dimethylamino; carboxy (lower) --dkylamino such as carbo-xymethyl- ⁇ unethylamino; dihydroxyboraneyl; tri(lower alkyl) ammonium such as trimethylammonium; glycosyloxy; heterocyclic carbonylamino such as (2-oxo- 1
  • the preferred polymer of the invention can be obtained by polymerization of a monomer of the formula (I) or its salt in -the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25, preferably 1:0.5 to 1:20 in the presence of a radical initiator
  • R 1 and R 3 are each as defined in the above, and R 2 and R 4 are each lower alkyl carbamoyl group, aryl carbamoyl group, lower alkoxycarbonyl group, heterocyclicoxycarbonyl group or heterocyclccarbonyl group, each of which may have one or more suitable substituent(s); tri (lower) alkylsilyl group; amino lower alkyl group which may have one or more suitable substituent(s); heterocyclic group which may have one or more suitable substituent(s); or carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.
  • the more preferred polymer of the invention can be obtained by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25, preferably 1:0.5 to 1:20 in the presence of a radical initiator
  • R 1 and R 3 are each as defined in the above, and
  • R 2 and R 4 are each lower alkyl carbamoyl group which may have one or more substituents selected from the group consisting of sulfo, hydroxy, carboxy, amino, sulfo (lower) alkylamino and carboxy(lower)a----tyla-mino, or lower alkoxycarbonyl group which may have one or more substituents selected from the group consisting of hydroxy, amino, lower alkylamino, glycosyloxy, heterocyclic carbonylamino and heterocyclic(lower)alkylaminocarbonylamino; tri(lower)alkylsilyl group; amino lower alkyl group which may have one or more suitable substituent(s); heterocyclic group which may have one or more suitable substituent(s); or carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.
  • Suitable salts of the polymers, monomers of the formula (I), the formula (la) and the formula (II) are conventional non-toxic salts such as salt with an alkali metal [e.g., lithium, sodium or potassium] and an alkaline earth metal [e.g., calcium or magnesium], ammonia, an organic base [e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'-dibenzylethylenediamine], an organic acid [e.g., formic acid, acetic acid, trifluoroacetic acid, aleic acid, tartaric acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid], an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid], an amino acid [e.g., arginine, aspartic acid or gluta
  • the preferred monomers of the formula (I) and the formula (II) are 2-glucosylethyl methacrylate (GEMA), N- tris(hydroxymethyl)methylacrylamide (NAT), methylcellulose acrylate (MCA) represented by the formula :
  • R 6 is hydrogen, methyl or vinylcarbonyl a d x is an integer of 1 or more, 2-aminoethyl methacrylate hydrochloride (AEM-HC1), allylamine hydrochloride (AL-Am-HCl), dimethylacrylamide (DM AA), acrylic acid (AA), (acryloylamino) (hydroxy) acetic acid (AHA), 4- acryloylmorpholine (AM), 2-(acryloylamino)-2-methyl-l-propanesulfonic acid (AMP), 3-(acryloylamino)phenylboronic acid (APB), [[3- (acryloylamino)propyl] (dimethyl) ammonio] acetate (APDAA), 3-[[3-
  • GEMA glycosyloxylethyl 2-methacrylate
  • HCAEM N- (hydro-xymethyl)ac ⁇ ylamide
  • HCAEM 2- ⁇ [(8-hydroxy-5- quinonnyl)carbonyl]am o ⁇ -ethyl 2-methylacrylate
  • HMTP-HC1 2- hy ⁇ -lroxy-3-(methac-yloyloxy)-N,N,N-trm chloride
  • IMA 2-[( ⁇ [2-(lH-imidazol-5- yl) ethyl] amino ⁇ carbonyl) amino] ethyl 2-methylacrylate
  • IMA lithium acrylate
  • LA 2-methylacrylic acid
  • MAA methyl 2-methylacrylate
  • MMA 3,6,9,12, 15, 18,21,24,27-nonaoxaoctacos- l-yl 2-methylacrylate
  • NM 2- ⁇ [(2-oxo-l,2-dihydro-4-pyrimi
  • an integer of 1 or more may be an integer of 1 to 20,000, in which the preferred one is an integer of 1 to 1,000, and more preferred one is 1 to 500, and the most preferred one is 1 to 100.
  • the preferred radical initiators are the ones having azo group in the molecule and the peroxides which may have perfluoroalkanoyl groups.
  • the peroxides having perfluoroalkanoyl groups are represented by the formula (III):
  • R 5 is a perfluoro (lower) alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more of fluorine atom(s).
  • the preferred radical initiators of the formula (III) are 2,3,3,3- tetrafluoro-2-(l,l,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide
  • PFPO-2 2,3,3,3-tetrafluoro-2-[l, l,2,3,3,3-hexafluoro-2-(l, 1,2,2,3,3,3- heptafluoropropoxy)propoxy]propanoyl peroxide (PFPO-3), trifluoroacetyl peroxide (FAP), 2,2,3,3,4,4,4-heptafluorobutanoyl peroxide (FBP), 2,3,3,3-tetraJluoro-2- ⁇ l, 1,2,3, 3,3-hexafluoro-2- [l, l,2,3,3,3-hexafluoro-2-(l, 1,2,2,3,3,3- heptafluoropropoxy) ⁇ ropoxy]propoxy ⁇ propanoyl peroxide (PFPO-4), , 2,4,4,5,7,7,8, 10, 10, 11, 13, 13, 14, 14, 15,15, 15-heptadecafluoro-2,5,8, 11- tetrakis(trifluoromethyl)
  • the polymers or their salts obtained by using the peroxides of the formula (III) as a radical initiator may be represented by the formula (IV) :
  • R 1 and R 3 are as defined in the above, and R 2 and R 4 are as defined in the above, and R 2 and/ or R 4 may be intramolecularly and/ or intermolecularly_ crosslinked with another R 2 or R 4
  • R 5 is as defined in the above, and n is an integer of 1 or more, and m is an integer of 0, 1 or more.
  • the preferred polymers of the formula (IV) are those wherein R 1 ,
  • R 3 , R 5 , n and m are each as defined in the above, and R 2 and R 4 are each lower alkyl carbamoyl group or lower alkoxycarbonyl group, each of which may have one or more suitable substituent(s), amino lower alkyl group or carboxy group which may be esterified by the residue of cellulose optionally. substituted with one or more lower alkyl and/ or lower alkenoyl, and R 2 and/ or R 4 may be intramolecularly and/ or intermolecularly crosslinked with another R 2 or R 4 .
  • the more preferred polymers (IV) are those wherein R 1 , R 3 , R 5 , n and m axe each as defined in the above, and R 2 and R 4 are each lower alkyl carbamoyl group which may have one or more hydroxy, lower alkoxycarbonyl group substituted with amino or glycosyloxy, amino lower alkyl group or carboxy group esterified by esterified and/ or etherified cellulose, and R 2 and/ or R 4 may be intramolecularly and/ or intermolecularly. crosslinked with another R 2 or R 4 .
  • the polymers of the formula (IV) can be obtained by polymerization of GEMA with AEM-HCl in the presence of PFPO-2 in the molar ratio of GEMA-AEM-HC1 being 1:2, 1: 1, 1:0.5, 1:5 or 1:20, polymerization of GEMA with AL-Am-HCl in the presence of PFPO-2 in the molar ratio of GEMA:AL-Am-HCl being 1:0.5, polymerization of NAT with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT:AEM-HC1 being 1:0.5, polymerization of MCA in the presence of PFPO-2, polymerization of MCA with AEM-HCl in the presence of PFPO-2 in the molar ratio of MCA:AEM-HC1 being 1:0.6 or 1:3, polymerization of MCA with AEM-HCl in the presence of PFPO-3 in the molar ratio of MCA: AEM-HCl being 1:3 or 1:4, polymerization of M
  • radical initiators having azo group or peroxides are 2,2'-azobis(2-amidinopropane) dihydrochlori.de (V-50), 2,2 , -diamidinyl-2,2'-azobutane dihydrochlori.de, 2,2'-diamidinyl-2,2'- azopentane dihydrochlori.de, 2,2'-bis(N-phenylamidinyl)-2,2'- azopropane dihydrochlori.de, 2,2'-bis(N-phenylamidinyl)-2,2'-azobutane dihydrochlori.de, 2,2'-bis(N,N-dime1 ⁇ iylair-idinyl)-2,2'-azopropane dihydrochloride, 2,2'-bis(N,N-d--jnethylamidinyl)-2,2'-azobutane dihydrochloride, 2,2'-bis(N,N-d--
  • VA-545, VA-546, VA-548, VA-041, VA-044 and VA-046B therefor can be purchased from Wako Pure Chemical Industries Ltd. as radical initiators having azo group.
  • the preferred polymer or its salt of the invention is the one obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator,
  • R 1 is hydrogen atom or lower al yl group
  • R 2 is lower alkyl carbamoyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, carboxy, sulfo, N,N-di(lower)alkyl-N- sulfonato (lower) alkylammonio and N,N-di(lower)alkyl-N- carboxylato (lower) alkylammonio
  • aryl group optionally substituted with dihydroxyboranyl
  • R* a is hydrogen atom or lower alkyl group
  • R 2 a is lower alkyl carbamoyl group
  • R 3 is hydrogen atom or lower alkyl group
  • R 4 is lower alkyl carbamoyl group optionally substituted with sulfonato; carboxy group; lower alkoxycarbonyl group optionally substituted with lower alkoxy in which the alkyl moiety may be interrupted by oxygen atom(s); carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl; amino (lower) alkyl group; heterocyclic carbonyl group; or tri(lower)alkylsilyl group, provided that when R 2 a and R 4 are the same, then R l a and R 3 are different from each other.
  • the polymerization is usually carried out in an organic solvent such as l, l,-dichloro-2,2,3,3,3-pentafluoropropane, 1,3-dichloro- 1,2,2,3,3-pentafluoropropane or any other organic solvent which does not adversely affect the reaction, or a mixture thereof or a heterogeneous mixed solvent thereof with water.
  • the reaction is usually carried out in the presence of a radical initiator at a temperature under cooling to warming, preferably at the temperature of 40°C to 50°C.
  • the polymer or its salt of the present invention can be intramolecularly and/ or intermolecularly crosslinked by a suitable crosslinking agent or without a crosslinking agent.
  • a suitable crosslinking agent or without a crosslinking agent.
  • An example of the partial structure of the crosslinked polymer is represented by the formula : wherein R 6 and x are each as defined in the above.
  • reaction condition can be referred to the Examples mentioned below.
  • the polymer prepared by the above process can be isolated and purified by a conventional method such as washing with an organic solvent, pulverization, recrystallization, chromatography, reprecipitation or the like. It is to be noted that the polymer of this invention may include one or more stereoisomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s), and all of such isomer(s) and mixture thereof are included within the scope of this invention.
  • isomerization or rearrangement of the polymers may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
  • a pharmaceutically acceptable salt of the polymer can be prepared, for example, by treating the polymer having amino group with
  • radiolabelled derivatives of the polymer which are useful for biological studies.
  • the polymers and pharmaceutically acceptable salts thereof are useful for the treatment and/ or prevention of various, diseases caused by accumulated phosphates such as hyperphosphoremia.
  • the phosphate solution (20mM Tris, lOmM Phosphoric acid) was adjusted to pH 7.0 with acetic acid.
  • Test polymer 25mg
  • the phosphate solution (20ml) were mixed, and then the mixture was shaken vigorously for an hour.
  • Resultant solution was centrifuged for 15 minutes (15,000 rp ) with Microcon Centrifugal filter device (MILLIPORE YM- 10).
  • the phosphate concentration of the filtered solution was determined spectrophotometrically by using a standard molybdate assay (Wako P- test).
  • the phosphate binding (%) was calculated by the formula:
  • Cini initial concentration of the phosphate before binding
  • Cbin concentration of the phosphate after binding
  • the polymers of the present invention have superior ability for binding phosphate which indicates that they have superior ability for adsorbing phosphate.
  • the polymer and its salt can be administered alone or in a form of a mixture, preferably, with a calcium compound such as calcium chloride, calcium carbonate and the like.
  • a pharmaceutical composition comprising a polymer or its salt as an active ingredient in association with a calcium compound is preferred in view point of the phosphate binding ability.
  • the active ingredient of this invention can be used in a form of a pharmaceutical preparation, for example, in solid or semisolid form, which contains a polymer as an active ingredient in admixture with a pharmaceutically acceptable, substantially non-toxic organic or inorganic carrier or excipient suitable for oral, parenteral such as intravenous, intramuscular, subcutaneous, intracavernous or intraarticular, external such as topical, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal applications.
  • parenteral such as intravenous, intramuscular, subcutaneous, intracavernous or intraarticular
  • external such as topical, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal applications.
  • the active ingredient may be compounded, for example, with the conventional non-toxic, pharmaceutically acceptable carriers or excipients for ointment, cream, plaster, tablets, pellets, capsules, suppositories, emulsion, suspension, aerosols, pills, powders, syrups, injections, troches, cataplasms, buccal tablets, sublingual tablets or any other form suitable for use.
  • carriers or excipients for ointment cream, plaster, tablets, pellets, capsules, suppositories, emulsion, suspension, aerosols, pills, powders, syrups, injections, troches, cataplasms, buccal tablets, sublingual tablets or any other form suitable for use.
  • the carriers which can be used are olive oil, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing the above-mentioned preparations.
  • auxiliary, stabilizing, thickening or coloring agents and perfumes may be used.
  • the active polymer is included in a pharmaceutical composition in an effective amount sufficient to show the desired effect.
  • a daily dose of about 0.01 mg-100 g, preferably 0.1 mg-50 g and more preferably 0.5 mg-10 g of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 nig, 5 mg, 10 mg, 50 mg, 1 g, 2.5 g and 5.0 g is generally administered.
  • Daily doses for chronic administration in humans is in the range of about 0.3 mg/body to 50 g/body.
  • This polymer causes gelation with water and DMSO(dimethylsulf oxide).
  • the gelation ability of this polymer was studied by measuring critical gel concentration (CGC, g/L) of this polymer in water or DMSO.
  • CGC in water and DMSO are 123 g/L and 173 g/L, respectively.
  • This polymer was insoluble in methanol, ethanol, tetrahydrofuran, chloroform, benzene, toluene, ethyl acetate, 1 : 1 mixed solvents of l,l-dichloro-2,2,3,3,3-pentafluoropropane and 1,3-dichloro- 1,2,2,3,3-pentailuoropropane, dimethylformamide, n-hexane, acetone or dichloromethane. Examples 3 to 7
  • Each polymer was prepared from monomers and a radical initiator in a similar manner to Example 1.
  • the kinds and molar ratio of the monomers and the radical initiator used in each Example are shown in Table 2.
  • Table 2 The kinds and molar ratio of the monomers and the radical initiator used in each Example are shown in Table 2.
  • PFPO-2 2,3,3,3-tetra-fluoro-2-(l, l,2,2,3,3,3-heptafluoropro ⁇ o-xy)propanoyl peroxide;
  • PFPO-3 2,3,3,3-tetrafluoro-2-[l, l,2,3 J 3,3-hexa-fluoro-2-(l,l,2,2,3,3,3-heptafluoropropoxy)propoxy]propanoyl peroxide;
  • GEMA 2-glycosyoxylethyl methacrylate ;
  • AEM-HCl 2-aminoethyl methacrylate hydrochloride;
  • AL-Am-HCl allylamine hydrochloride;
  • NAT N-tris(hydroxymethyl)methylacrylamide;
  • CGC critical gel concentration
  • entafluoropropane and 1,3- dichloro-l,2,2,3,3-pentafluoropropane 150 g was added to an aqueous solution (100 g) of methylcellulose acrylate (MCA: 1.00 g; Monomer- Polymer 85 Dajac Labs., Inc.) and 2-aminoethyl methacrylate hydrochloride (AEM-HCl: 2.9 mmol).
  • MCA methylcellulose acrylate
  • AEM-HCl 2-aminoethyl methacrylate hydrochloride
  • the critical gel concentration (CGC) of this polymer in water is 107 g/L.
  • Example 9 Each polymer was prepared from monomers and a radical initiator in a similar manner to Example 8. The kinds and molar ratio of the monomers and the radical initiator used in each Example are shown in Table 4. Table 4
  • PFPO-2 2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide;
  • PFPO-3 2,3,3,3-tetrafluoro-2-[l,l,2,3,3,3-hexa-fluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)propoxy]propanoyl peroxide;
  • MCA methylcellulose acrylate
  • AEM-HCl 2-aminoethyl methacrylate hydrochloride
  • DMAA dimethylacrylamide
  • a 50% aqueous solution of GEMA (5.85 g, 10 mmol) was added to a solution of AEM-HCl (1.66 g, 10 mmol) and 2,2'-azobis(2- amidinopropane) dihydrochloride (V-50, 0.542 g) in water (16.56 g).
  • Each polymer was prepared from monomers and a radical initiator in a similar manner to Example 20.
  • the kinds and molar ratio of the monomers and the radical initiator used in each Example are shown in Table 6.
  • PFPO-2 2,3,3,3-tetrafluoro-2-(l, 1,2,2,3,3,3- heptafluoropropoxy)propanoyl peroxide
  • PFPO-3 2,3,3,3-tetrafluoro-2-[l,l,2,3,3,3-hexafluoro-2-(l, 1,2,2,3,3,3- heptafluoropropoxy)propoxy]propanoyl peroxide
  • V-50 2,2'-azobis(2-aminopropane)dihydrochloride
  • FAP trifluoroacetyl peroxide
  • FBP 2,2,3,3,4,4,4-heptafluorobutanoyl peroxide
  • PFPO-4 2,3,3,3-tetrafluoro-2- ⁇ l, l,2,3,3,3-hexafluoro-2-[l, 1,2,3,3,3- hexafluoro-2-(l, 1,2,2,3,3, 3- heptafluoropropoxy
  • AEM-HCl 2-aminoethyl methacrylate hydrochloride
  • AHA (acryloylamino) (hydroxy) acetic acid
  • AL-Am-HCl allylamine hydrochloride
  • AMP 2-(acryloylamino)-2-methyl- 1-propanesulfonic acid
  • APB 3-(acryloylamino)phenylboronic acid
  • APDAA [[3-(acryloylamino)propyl] (dimethyl)ammonio]acetate
  • APDAP 3-[[3-(acryloyla ⁇ nino)propyl](dimethyl)ammonio]-l- propanesulfonate
  • CDA calcium diacrylate
  • CQA 5-chloro-8-quinolinyl acrylate
  • DCAEM 2- ⁇ [(2,4-dioxo-3,4-dihydro-l(2H)- pyri-mid-inyl)c---u:bonyl]a-mino ⁇ ethyl 2-methylacrylate
  • DMAA N,N-dime&ylac ⁇ ylamide
  • FCAEM 2- ⁇ [(5-fluoro-2,4-dioxo-3,4-dihydro-l(2H)- pyrirnidinyl)carbonyl]a ⁇ nino ⁇ ethyl 2-methylaceylate
  • GEMA 2-(glycosyloxyl)ethyl 2-methacrylate
  • HA N-(hydroxymethyl)acrylamide
  • HCAEM 2- ⁇ [(8-hydroxy-5-quino--inyl)carbonyl]amino ⁇ -ethyl 2- methylacrylate
  • HMTP-HCl 2-hydroxy-3-(methac ⁇ -yloyloxy)-N,N,N-trimethyl- 1- propanaininium chloride
  • IMA 2-[( ⁇ [2-(lH-imida ⁇ ol-5-yl)ethyl]amino ⁇ carbonyl)amino]ethyl 2- methylacrylate
  • LA lithium acrylate
  • MAA 2-methylacrylic acid
  • ' MMA methyl 2-methylacrylate
  • MCA methylcellulose acrylate
  • NAT N- [2 -hydroxy- 1 , 1 -bis (hydroxymethyl) ethyl] acrylarnide, NM: 3,6,9, 12, 15, 18,21,24,27-nonaoxaoctacos-l-yl 2-methylacrylate, • OCAEM: 2- ⁇ [(2-oxo-l,2-dihydro-4-pyrimidinyl)carbonyl]amino ⁇ ethyl 2- methylacrylate,
  • Preparation 1 The polymer hydrochloride (200mg) obtained in Example 1 and calcium carbonate (2 lmg) were homogeneously mixed in a mortar. The mixture was put into a test tube to which was added water (0.88 ml) to give a gel. Thus obtained wet gel was dried by using an aspirator and further dried at 50°C in vacuo for one day to give white gel-powder containing calcium carbonate.
  • Example 14 The polymer hydrochloride (105 mg) obtained in Example 14 was treated in a similar manner to Preparation 11 to give white gel-powder containing calcium chloride.
  • Example 11 Each polymer hydrochloride (105 mg) ' obtained in Example 11, 12 and 14 was treated in a similar manner to Preparation 13 to give white gel --powder containing calcium chloride.

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Abstract

L'invention concerne un polymère ou un sel de celui-ci, pouvant être obtenus par polymérisation d'un monomère représenté par la formule (I), ou son sel, en présence d'un initiateur radical, ou par polymérisation d'un monomère représenté par la formule (I), ou son sel, avec un monomère représenté par la formule (II), ou son sel, selon un rapport molaire de (I):(II), ou 1:0,1 à 1:25 en présence d'un initiateur radical, R1 et R3 étant chacun un atome d'hydrogène ou un groupe alkyle inférieur, R2 et R4 étant chacun un groupe acyle, un groupe silyle aliphatique, un groupe amino alkyle inférieur pouvant comprendre un ou plusieurs substituants adaptés, un groupe hétérocyclique pouvant comprendre un ou plusieurs substituants adaptés, ou un groupe carboxy estérifié par un reste de cellulose éventuellement substitué par un ou plusieurs alkyles inférieurs et/ou alcényles inférieurs.
PCT/JP2001/007958 2000-10-18 2001-09-13 Polymere et son utilisation WO2002032974A2 (fr)

Priority Applications (1)

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AU2001286228A AU2001286228A1 (en) 2000-10-18 2001-09-13 Polymer and its use for the treatment and/or prevention of hyperphosphoremia

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AUPR0850 2000-10-18
AUPR0850A AUPR085000A0 (en) 2000-10-18 2000-10-18 Fluro-polymer and its use
AUPR3754 2001-03-15
AUPR3754A AUPR375401A0 (en) 2001-03-15 2001-03-15 Fluoro-polymer and its use
AUPR7382A AUPR738201A0 (en) 2001-08-30 2001-08-30 Polymer and its use
AUPR7382 2001-08-30

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41316E1 (en) 2004-03-22 2010-05-04 Han Ting Chang Crosslinked amine polymers
US7718746B2 (en) 2003-11-03 2010-05-18 Ilypsa, Inc. Anion-binding polymers and uses thereof
US7767768B2 (en) 2003-11-03 2010-08-03 Ilypsa, Inc. Crosslinked amine polymers
WO2014096196A1 (fr) * 2012-12-20 2014-06-26 Novartis Ag Adsorbant phosphate à base de fer(iii) administré par voie orale pour le traitement de l'anémie par carence en fer chez le chat présentant une atteinte rénale chronique
DE102013221209A1 (de) * 2013-10-18 2015-04-23 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Siliconhydrogel, Verfahren zu dessen Herstellung, Formteil hieraus sowie Verwendungszwecke

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005184A2 (fr) * 1993-08-11 1995-02-23 Geltex Pharmaceuticals, Inc. Polymeres fixant les phosphates pour administration orale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005184A2 (fr) * 1993-08-11 1995-02-23 Geltex Pharmaceuticals, Inc. Polymeres fixant les phosphates pour administration orale

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718746B2 (en) 2003-11-03 2010-05-18 Ilypsa, Inc. Anion-binding polymers and uses thereof
US7767768B2 (en) 2003-11-03 2010-08-03 Ilypsa, Inc. Crosslinked amine polymers
USRE41316E1 (en) 2004-03-22 2010-05-04 Han Ting Chang 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
US8349305B2 (en) 2004-03-22 2013-01-08 Ilypsa, Inc. Crosslinked amine polymers
WO2014096196A1 (fr) * 2012-12-20 2014-06-26 Novartis Ag Adsorbant phosphate à base de fer(iii) administré par voie orale pour le traitement de l'anémie par carence en fer chez le chat présentant une atteinte rénale chronique
AU2013366652B2 (en) * 2012-12-20 2016-05-19 Elanco Tiergesundheit Ag An oral iron (III) based phosphate adsorbent for treating iron-deficiency anemia in cats with chronic kidney disease
DE102013221209A1 (de) * 2013-10-18 2015-04-23 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Siliconhydrogel, Verfahren zu dessen Herstellung, Formteil hieraus sowie Verwendungszwecke
DE102013221209B4 (de) * 2013-10-18 2019-09-26 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Siliconhydrogel, Verfahren zu dessen Herstellung, Formteil hieraus sowie Verwendungszwecke

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