EP1615940A1 - Monomeres polymerisables et leur procede de preparation - Google Patents

Monomeres polymerisables et leur procede de preparation

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Publication number
EP1615940A1
EP1615940A1 EP03816519A EP03816519A EP1615940A1 EP 1615940 A1 EP1615940 A1 EP 1615940A1 EP 03816519 A EP03816519 A EP 03816519A EP 03816519 A EP03816519 A EP 03816519A EP 1615940 A1 EP1615940 A1 EP 1615940A1
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European Patent Office
Prior art keywords
acid
spacer
amino
solution
monomeric
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EP03816519A
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German (de)
English (en)
Inventor
Mohan Gopalkrishna Kulkarni
Jayant Jagannath Khandare
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids

Definitions

  • This invention relates to polymerizable monomers containing N-Acety! Glucosamine (NAG) of formula (1) herein below
  • Y Formula 1 wherein, R is H, CH 3 , C 2 H 5 or CeHs, X is based on 4-Amino Butyric Acid(4-ABA), 6-Amino Caproic Acid(6-ACA), 8 Amino Octanoic Acid(8-AOA),IO-Amino Decanoic Acid(IO- ADA), II- Amino Undecanoic Acid(lI-ADA); Y is selected from the group consisting of N- Acetyl Glucosamine, mannose, galactose and sialic acid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuninose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellobiose, cellulose and amylose.
  • the present invention relates to the said monomers containing carbohydrate ligands and preparation thereof through the specific linkage mentioned herein. Still more particularly it relates to monomers which bind more strongly to lysozyme than NAG itself.
  • RBC Red-, Blood Cells
  • Protein carbohydrate interactions are of low affinity. If relative density and spatial arrangement of ligands incorporated is optimized, then the binding can be substantially enhanced.
  • the enhanced interaction between monomeric ligand with a specific binding site of biomolecule can also find applications in affinity separations, drug delivery and biotechnology. To imitate and exploit this mechanism there- is a need to devise simple methodologies for the synthesis of the polymerizable ligands, which will enhance substrate ligand interactions.
  • Site-specific ligand conjugates are interactive molecules, and are useful in im unoassays and biomolecule separations.
  • the interacting molecules can be proteins or peptides, antibodies, enzymes, polysaccharides or glycoproteins that specifically bind to other substrate receptors in the suitable environment.
  • a ligand so bound can be displaced from the binding site by altering environmental conditions.
  • Sharon et al. (Science 246:227-234,1989) reported that carbohydrate portions of glyco-conjugate molecules were an important entity in carbohydrate biology.
  • Advantage of carbohydrate modification lies in that it may impart change in physical characteristics such as solubility, stability, activity, antibody recognition and susceptibility to enzymes.
  • Damschroder et al. (U.S. Patent 2,548,520,1951) disclosed high molecular weight materials prepared by copolymerizing proteins conjugated with unsaturated monomers or proteins conjugated with preformed polymers. Synthesis of these high molecular weight materials generally requires temperatures up to 100 0 C. Such high temperatures are not well tolerated by most of the proteins. Thus the methods described are unsuitable for producing polymers of biologically active molecules. Ja wornk ,et at. (U.S. Pat. No. 3,969,287, 1976) reports a method for the preparation of carrier-bound proteins, wherein the protein is reacted with a monomer containing at least one double bond capable of copolymerization. The carrier is provided as a water insoluble solid or is produced in situ by the polymerization of water-soluble monomers in the presence of the protein monomer conjugate.
  • the proteins utilized in the method of this invention are typically enzymes.
  • the protein may be conjugated with a polymer to form a polymer protein conjugate.
  • the extent of conjugation of proteins in this is limited by the. steric considerations.
  • the conjugation of the ligand along the polymer chain cannot be precisely' arranged, controlled / reproduced.
  • Monomers and oligomers can be covalently bonded directly to selected ligands through chemical spacer arm to form monomer, oligomer conjugates. .This can be followed by the copolymerization of these conjugates with other monomers. Using controlled chemical synthesis methods it is possible to control the spacing, steric accessibility, number of ligand molecules in the polymer molecular weight, density, solubility and physical structure of the polymeric conjugates. The method thus provides unique advantages in various applications.
  • the efficiency of ligand binding with the specific substrates receptors can be quantified in various terms such as binding constants (Kb), association constants (Ka) or the relative inhibition (150) in presence of the substrates.
  • influenza virus hemagglutinin mediates the initial step of infection. This involves binding between the hemagglutinin and the sialic acid residues on the cell surface receptors on the nasal epithelial cells.
  • the carbohydrates such as NAG serve as ligands for lectins and lysozyme.
  • Roy et al. J.Chem.Soc.Chem.Comm., 1611-1613, 1992
  • JEhe N-acryloyl precursors and the acrylamide were ⁇ sed as effector molecules to provide specific properties such as hydrophobicity and mimicking tyrosine residues of proteins.
  • the polymeric fucosides are resistant to an enzyme neuraminidase found on the surface of influenza virus.
  • the viruses also cleave sialic acid groups on the Red Blood Cell surfaces from molecules that bind to the surface of the virus, and thereby destroy the cell stability.
  • Recent literature highlights the advantages of polyvalent interactions and their application in medicine and biotechnology.
  • the fucoside sialic acid moities can be linked to polymer for the treatment of rotavirus (Mandeville, III, et al., United States Patent 6,187,762, 2001). These moietip can inhibit or. prevent rotavirus infection in mammals and humans.
  • Chitosan (Formula 4) is a linear, binary heteropolysaccharide and consists of 2- acetoamido-2-deoxy- ⁇ - D-glucose( GlcNAc;A -unit) and 2-amino- 2-deoxy - ⁇ - D glucose (GlcNAc, D-unit).
  • the active site of lysozyme comprises subsites designated A-F. Specific binding of chitosan sequences to lysozyme begins with binding of the NAG units in the sub site C.
  • natural ligands derived from glucose are susceptible to microbial growth.
  • the main object of the present invention is to provide polymerizable monomers for applications in medicine and biotechnology.
  • Another object is to provide a convenient method of preparation of reactive polymers of various molecular weights with the ligands like NAG, mannose, galactose or sialic ac id, fructose, ribulose, erythro lose, xylulose, psicose,sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellabiose, cellulose and amylose.
  • the ligands like NAG, mannose, galactose or sialic ac id, fructose, ribulose, erythro lose, xylulose, psicose,sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, iso
  • Still another object is to provide a convenient method of preparation of monomers, containing a ligand.
  • Yet another object is to provide a method of preparation of monomers containing NAG for enhanced interactions.
  • Still another object is to provide more stable hgands for the interactions with biomolecules than the natural polymers such as chitin and chitosan containing NAG.
  • the present invention provides polymerizable monomers for a biomolecular target and method for synthesis thereof, which exhibits selective binding to the target enzyme/ protein.
  • the present invention also provides a method for obtaining affinity ligand useful for isolating target biomolecule from a solution.
  • the polymerizable Hgands may be further oligomerized or polymerized and may posses a terminal functional group. Further, these can be copolymerized with other comonomers to offer copolymers bearing a wide range of polymer architecture than those realized in the past.
  • These ligands containing N-Acetyl Glucosamine are easy to prepare and are resistant to degradation are reusable, stable and free from microbial contamination.
  • the present invention provides a polymerizable monomer of formula 1
  • Y Formula 1 wherein, R is H, CH 3 , C 2 H 5 , C ⁇ Hs; X is a based on spacer exemplified by 4-Amino Butyric Acid(4-ABA), 6-Amino Caproic Acid(6-ACA).
  • Y is a carbohydrate ligand selected from the group consisting of N-Acetyl Glucosamine ,mannose, galactose and sialicacid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellobiose, cellulose and amylose.
  • the present invention also provides a process for the preparation of the polymerizable monomer of formula 1
  • Y Formula 1 wherein, R is H, CH 3 , C 2 H5, C 6 H 5 ;
  • X is a based on spacer exemplified by 4-Amino Butyric Acid(4-ABA), 6-Amino Caproic Acid(6-ACA), 8-Amino Octanoic Acid( ⁇ -AOA), IO-Amino Decanoic Acid(lO-ADA), II-Amino Undecanoic Acid(l l-ADA);
  • Y is a carbohydrate ligand selected from the group consisting of N-Acetyl Glucosamine , mannose, galactose and sialicacid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cell
  • the polymerizable monomeric acid chloride is selected from methacryloyl or acryioyl chloride.
  • the alkali comprises a 10 to 20% solution of hydroxide, bicarbonate or carbonate of alkali metal exemplified by NaOH, KOH, NaHCO 3 , Na 2 CO 3 .
  • the spacer includes bifunctional compounds having a reactive site for bonding with the monomeric acid chloride and a reactive site for bonding with carbohydrate ligand, functional groups exemplified by OH, COOH or NH 2 such as 4-Amino Butyric (4-ABA)Acid ,6-Amino Caproic Acid (6-ACA), 10-Amino Decanoic
  • the solvent used for solvent extraction of unreacted monomeric spacer is non solvent to the monomeric spacer exemplified by ethyl or methyl acetate.
  • the acidification is carried out using mineral acids having concentration of 5 to 20%.
  • organic solvent used to dissolve the conjugate is selected from dimethyl formamide, tetra hydro furan and di-methyl sulfoxide.
  • carbohydrate ligand is selected from NAG, sialic acid, mannose and galactose.
  • the coupling agent used is selected from Dicyclohexyl Carbodiimide (DCC), I-Cyclohexyl 3 -(2- Morpholinoethyl) Carbodiimide metho-p- toluenesulfonate(CMC), and I-Ethyl-3-(3-Dimethylamino-propyl) Carbodiimide(EDC).
  • the non-solvent used to precipitate the polymerizable monomer is selected from acetone, diethyl ether and hexane.
  • the molar ratio of monomeric acid chloride to amino acid used for the synthesis of the monomer is 1 : 1.
  • the molar ratio of coupling agent for condensation of monomeric spacer to carbohydrate ligand is 1: 1
  • the molar ratios of polymerizable monomeric acid chloride to spacer is in the range from 0.1: 1 to 1: 0.1, preferably 0.5 to 1 to 1:0.5, more preferably from 0.8: 1 to 1 : 0.8.
  • the conjugation of the monomer with the ligand is effected through a spacer.
  • the "spacer” provides greater accessibility to the ligand conjugate for binding with receptor biomolecule.
  • polymerizable acid chloride is linked to NAG thro ⁇ gh CH20H group, a feature not present in chitosan, chitin and/or other derivatives of NAG so far reported in the literature.
  • NAG is derived from chitosan which is a linear, binary heteropolysaccharide and consists 2 -acetoamido-2-deoxy- ⁇ -D-glucose (GlcNAc ; A-unit) and 2-amino 2-deoxy- ⁇ -D- glucose (GlcNAc, D-unit).
  • Chitosan is a powerful natural ligand, which binds to lysozyme through the NAG residues. But it suffers from three major limitations 1) Chitosan is insoluble at neutral pH, which limits many applications. 2) Chitosan undergoes the transglycosylation and mutarotation, which substantially reduces its activity and efficiency 3) ' Chitosan is hydrolyzed by lysozyme.
  • the present invention provides a simple process for preparation of polymerizable monomers comprising NAG, which can be exploited for " multivalent interactions.
  • the merits of the approach have been highlighted using NAG as an illustration.
  • Various methods have been reported in the past for the synthesis of glycoconjugate oligomers and clusters for the receptor binding activity.
  • Nishimora et al. (Macromolecules., 27, 4876- 4880, 1994) synthesized clustering sugar homopolymers from acrylamidoalkyl glycosides of N-Acetyl-D-Glucosamine.
  • binding to WGA was enhanced.
  • the methodology described by us is useful to synthesize the polyvalent carbohydrate conjugates to enhance ligand substrate interactions. Further the approach can be extended to other ligands such as sialic acid, mannose and galactose.
  • the present invention provides polymerizable monomers having formulae (1)
  • Y Formula 1 wherein, R is H, CH 3 , C 2 H 5 , CeH 5 ;
  • X is a based_on,.spacer exemplified by 4-Amino Butyric Acid(4-ABA), 6-Amino Caproic Acid(6-ACA), 8-Amino Octanoic Acid(S-AOA), IO-Amino Decanoic Acid(lO-ADA), II-Amino Undecanoic Acid(l l-ADA);
  • Y is a carbohydrate ligand such as N-Acetyl Glucosamine ,mannose, galactose and sialicacid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cello
  • the present invention also provides a process for the preparation of the polymerizable monomers mentioned above which comprises dissolving a polymerizable monomeric acid chloride in a solution of an alkali, separately preparing an aqueous solution of a spacer, bringing the temperature of the solutions to 5 to 10°C, adding drop wise the solution of polymerizable monomeric acid chloride to the solution of the spacer, maintaining pH of the mixture 7.4 to 7.8 by the addition of the alkali solution, and the temperature 5 to 10°C during addition removing the unreacted monomeric acid chloride by solvent extraction, acidifying the reaction mixture to pH 5 to 5.5, and solvent extracting the reaction mixture, precipitating using a non solvent to obtain the monomeric-spacer conjugate, drying under vacuum at room temperature, dissolving the conjugate in an organic solvent, adding to this a carbohydrate ligand, adding to this reaction mixture a coupling agent, allowing the reaction for a period of 24 to 48 hrs at room temperature, removing the unreacted coupling agent, treating the clear
  • the polymerizable monomeric acid chloride is preferably selected from methacryloyl or acryioyl chloride.
  • the alkali comprises 10 to 20% solution of hydroxide, bicarbonate or carbonate of alkali metal exemplified by NaOH, KOH, NaHC0 3 , Na 2 CO 3 .
  • the spacer may include bifunctional compounds having a reactive site for bonding with the monomeric acid chloride and a reactive site for bonding with carbohydrate ligand, functional groups exemplified by OH, COOH or NH 2 such as 4-Amino Butyric (4-AB A)Acid ,6-Amino Caproic Acid (6-ACA), 10- Amino Decanoic Acid (10-ADA), 1, 4-diaminobutane, hexamethylenediamine, 1,4-butanediol.
  • the solvent used for solvent extraction of unreacted monomeric spacer may be non solvent to the monomeric spacer exemplified by ethyl or methyl acetate.
  • the acidification may be done by using mineral acids having concentration of 5 to 20%.
  • the organic solvent used to dissolve the conjugate may be such as dimethyl formamide, tetra hydro furan or di-methyl sulfoxide.
  • the carbohydrate ligand is NAG, sialic acid, mannose or galactose.
  • the coupling agent used is selected from compounds such as Di Cyclohexyl Carbodiimide (DCC), I-Cyclohexyl 3 -(2- Morpholinoethyl) Carbodiimide metho- p-toluenesulfonate(CMC), I-Ethyl-3-(3-Dimethylamino-propyl) Carbod ⁇ mide(EDC).
  • the non solvent used to precipitate the polymerizable monomer is selected from acetone, diethyl ether or hexane.
  • the molar ratio of monomeric acid chloride to amino acid used for the synthesis of the monomer is 1: 1.
  • the molar ratio of coupling agent for condensation of monomeric spacer to carbohydrate ligand is 1: 1.
  • the molar ratios of polymerizable monomeric acid chloride to spacer are in the. range from 0.1: 1 to 1: 0.1, preferably 0.5 to 1 to 1:0.5, more preferably from 0.8: 1 to 1: 0.8.
  • the conjugation of the monomer with the ligand is preferably effected through a spacer.
  • the "spacer” provides greater accessibility -to the ligand conjugate for binding with receptor biomolecule.
  • the polymerizable acid chloride is linked to NAG through
  • CH 2 OH group a feature not present in chitosan, chitin and/or other derivatives of NAG so far reported in the literature.
  • the method used for estimation of the relative inhibition is in terms of 1 50 mM and I max mM values.
  • the binding between lysozyme and the monomeric ligand-containing NAG is enhanced.
  • the process reported herein for the incorporation of NAG into monomers is relatively simple. Besides the monomers are effective at very low ligand concentration, which is an advantage when the ligands under consideration are expensive e.g. sialic acid.
  • the polymers containing multiple ligands can potentially interact with multiple receptors simultaneously thereby enhancing the binding to lysozyme.
  • the ability of these ligands to inhibit enzyme activity provides new ways of developing effective inhibitors.
  • the monomers synthesized indicate enhanced substrate ligand interactions and can be used in diverse applications such as in immunoassays and affinity separations.
  • the present invention relates to the monomers containing carbohydrate moieties and preparation thereof.
  • the monomer may comprise a spacer arm, which is inserted between the vinyl group and the ligand. These monomers may be used for the synthesis of homopolymers, oligomers and copolymers for the recovery of biomolecules.
  • the polymers comprising carbohydrate monomer conjugates can also further be used in the treatment of bacterial or viral infections, and are expected not to cause drug resistance.
  • Monomers containing NAG exhibit enhanced hydrolytic stability and water solubility than natural polymers containing NAG such as chitosan .
  • the monomers containing NAG may be used for polymerization or oligomerization. They may be also used as anti infective agents both for prevention and treatment of diseases, recovery of the naturally occurring as well as genetically manipulated biomolecules.
  • the present invention relates to the polymerizable monomers containing NAG which can be converted to homo and copolymers for applications in medicine and biotechnology.
  • a further aspect of the invention is to prepare monomeric NAG comprising a spacer arm. The advantage of incorporating spacer arms is enhanced accessibility of the ligand to active site of the enzyme.
  • the term "monomer” means any polymerizable organic compound, which is capable of forming covalent linkages i.e., polymerization under the appropriate conditions can be used such as acrylic or methacrylic acid, acryioyl or methacryloyl chloride, glycidyl acrylate or methacrylate, glycerol acrylate or methacrylate, allyl chloride; hydroxy-lower-alky-1- acrylates, such as 2-hydroxyethyl methacrylate or 3-hydroxypropyl methacrylate, and amino- lower-alkyl acrylates, such as 2-amino-ethyl methacrylate. Monomers, which are soluble in water or water/polar organic solvent mixtures, are particularly preferred.
  • a representative ligand used here is Methacryloyl N-Acetyl Glucosamine of formula 5 as shown herein below but does not limit the scope of invention.
  • sialic acid ligands are known to bind to influenza virus and rotavirus.
  • polymers comprising sialic acid can be expected to bind to the two viruses more strongly than the corresponding monomers.
  • the present invention provides methods for the preparation of polymerizable monomers containing N-Acetyl Glucosamine, which can be oligomerized or polymerized as desired. These monomers provide improved binding and inhibition of biomolecules and their efficacy can be further enhanced by polymerization.
  • the polymerizable monomers provided by the present invention may comprise a spacer arm, which is inserted between the vinyl group and the carbohydrate ligand. These monomers are useful for the synthesis of homopolymers, oligomers and copolymers for inhibition of viral infections and the recoveries of biomolecular.
  • Example 1 Preparation of Acryioyl N-Acetyl Glucosamine (Ac. NAG) 11.1 gm. N-Acetyl Glucosamine and 4.2 gm. of sodium bicarbonate was dissolved in a beaker, which was equipped with a dropping funnel and a pH meter. The clear solution was stirred continuously on a magnetic stirrer at 5°C. 5 ml Acryioyl Chloride in 5 ml of dichloromethane was added drop wise.
  • binding constants of polymerizable monomers are summarized in Table 1 wherein, N-Acetyl Glucosamine has binding constant 5.24 x 102 where as that for the monomer Ac. NAG is 7.07 x 104. The increase in binding constant is 74 times.
  • Micrococcus lysodeikticus is a substrate for the enzyme lysozyme! Relative binding of monomers and monomers linked to NAG through the spacer arm was estimated by using a procedure reported by Neuberger and Wilson (1967).
  • the relative inhibition of lysozyme in terms of I 50 for monomer NAG is 74.00 mM and has decreased to 14.81 mM ,which is almost 5 times lower. Whereas the I max has decreased from 55.29 to 50 for the monomer containing NAG.
  • I max has decreased from 55.29 mM to 14.81 mM (Table 2).
  • the relative inhibition I 50 has decreased from 74 mM to 0.035 mM which is almost to 2110 folds lower than that for NAG indicating enhanced efficacy of inhibition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne des monomères polymérisables pour des applications en médecine et en biotechnologie, ainsi que des synthèses de ceux-ci. Les ligands polymérisables contenant du N-acétylglucosamine se lient plus fortement à la lysozyme que le NAG lui-même. La liaison est en outre renforcée en introduisant dans la structure un bras espaceur, par exemple, l'acide 6-aminocaproïque (6-ACA). Les ligands conjugués peuvent être utilisés pour la prévention et le traitement d'infections bactériennes et virales. En outre, ces ligands peuvent être couplés à des polymères sensibles à des stimuli, et utilisés pour la récupération de biomolécules. La méthodologie peut s'étendre à d'autres ligands, tels que l'acide sialique et aux polymères correspondants pour la prévention d'infections par virus grippal et par les rotavirus.
EP03816519A 2003-03-31 2003-03-31 Monomeres polymerisables et leur procede de preparation Withdrawn EP1615940A1 (fr)

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CN101812490B (zh) * 2009-02-20 2013-09-11 元智大学 一种微生物生产葡萄糖胺的方法
CN102002077B (zh) * 2010-01-26 2014-08-27 深圳伯美生物医药有限公司 一种唾液酸-蛋氨酸锌新型偶联物、制备工艺及其应用
CN107602634A (zh) * 2017-09-19 2018-01-19 佛山科学技术学院 一种三糖的合成方法
CN111333158B (zh) * 2020-03-12 2023-04-07 江苏美淼环保科技有限公司 抑菌型abs异相离子交换膜及其制备方法和应用

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WO1994014823A1 (fr) * 1992-12-21 1994-07-07 University Of Iowa Research Foundation Polymeres a base de sucre
EP0668294B1 (fr) * 1994-02-15 1999-08-18 Novartis AG Dérivés insaturés d'hydrates de carbone, leurs polymères et leurs utilisations
US5891862A (en) * 1996-03-15 1999-04-06 Geltex Pharmaceuticals, Inc. Polyvalent polymers for the treatment of rotavirus infection
DE19854186A1 (de) * 1998-11-24 2000-05-25 Wacker Chemie Gmbh Grenzflächenaktive Organosiliciumverbindungen

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