EP1196181A1 - Fat-binding polymers, optionally combined with lipase inhibitors - Google Patents
Fat-binding polymers, optionally combined with lipase inhibitorsInfo
- Publication number
- EP1196181A1 EP1196181A1 EP99934037A EP99934037A EP1196181A1 EP 1196181 A1 EP1196181 A1 EP 1196181A1 EP 99934037 A EP99934037 A EP 99934037A EP 99934037 A EP99934037 A EP 99934037A EP 1196181 A1 EP1196181 A1 EP 1196181A1
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- European Patent Office
- Prior art keywords
- polymer
- mammal
- combination
- formula
- alkyl chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
-
- 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
Definitions
- Anorectic agents such as dextroamphetamine, the combination of the non- amphetamine drugs phentermine and fenfluramine ("Phen-Fen”) and dexfenfluramine (Redux) alone, are associated with serious side effects.
- Indigestible materials such as OLESTRATM, mineral oil or neopentyl esters (see U.S. Patent No. 2,962,419) have been proposed as substitutes for dietary fat.
- Garcinia acid and derivatives thereof have been described as treating obesity by interfering with fatty acid synthesis.
- Swellable crosslinked vinyl pyridine resins have been described as appetite suppressants via the mechanism of providing non-nutritive bulk, as in U.S. Patent 2,923,662. Surgical techniques, such as temporary ileal bypass surgery, are employed in extreme cases.
- the present invention relates to a method for treating obesity, a method for reducing the abso ⁇ tion of dietary fat, and a method for treating hypertriglyceridemia in a patient and to particular polymers for use in the methods or in a manufacture of a medicament.
- the methods comprise the step of orally administering to a mammal, such as a human, a therapeutically effective amount of a fat-binding polymer.
- a fat-binding polymer of the invention facilitates the excretion of fat from the body without digestion, with minimal side effects and low toxicity.
- the fat-binding polymers are administered in combination with a therapeutically effective amount of a lipase inhibitor, such as the pancreatic lipase inhibitors described in U.S. Patent No. 4,598,089 to Hadvary et al.
- a lipase inhibitor such as the pancreatic lipase inhibitors described in U.S. Patent No. 4,598,089 to Hadvary et al.
- the combination administration can reduce undesirable side effects often encountered when lipase inhibitors, in particular, the pancreatic lipase inhibitors lipstatin and tetrahydrolipstatin are administered alone.
- a serious side effect resulting from the administration of a lipase inhibitor is steatorrhea, or fatty stools.
- the fat-binding polymers of the invention comprise at least one fat-binding region.
- a fat-binding region can include a region having a positive charge, a region which is hydrophobic or a region having a positive charge and which is hydrophobic.
- the fat-binding polymer is an aliphatic polymer selected from the group consisting of polyalkylacrylates, polyacrylamides, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N- alkylmethacrylamides, substituted derivatives thereof and copolymers thereof.
- the substituted derivatives of the polymers can be characterized by one or more substituents, such as substituted or unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups.
- Suitable substituents to employ on the alkyl or aryl groups include, but are not limited to, cationic or neutral groups, such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, and ammonium groups.
- the polymer can be poly(dimethylamino propylacrylamide), poly(trimethylammonium ethylacrylate), poly(trimethylammonium ethyl methacrylate), poly(trimethylammonium propyl acrylamide), poly(dodecyl acrylate), poly(octadecyl acrylate), poly(octadecyl methacrylate) and copolymers thereof.
- the fat binding polymer is a synthetic amine polymer and pharmaceutically acceptable salts thereof.
- Amine polymers (or salts thereof) suitable for use in the invention include, but are not limited to, substitued or unsubstituted polymers or copolymers of the following monomers: allylamine, diallyldimethyl ammonium, ethyleneimine, vinylamine, diallylamine, vinylimidazole and diallylmethylamine.
- the fat binding polymer is an amine derivative of an anhydride containing polymer.
- the fat-binding polymer is a hydroxyl-containing polymer, for example, poly(vinylalcohol).
- the fat-binding polymer is an amine-containing polymer wherein one or more hydrophobic regions are bound to a portion of the amine nitrogens of the amine polymer. In a particular embodiment, between about 1 and about 60 percent of the amine nitrogens are substituted, preferably between about 1 and about 30 percent.
- the hydrophobic region of the fat-binding polymer can include a hydrophobic moiety, for example, a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least four carbons.
- the hydrophobic moiety is an alkyl group of between about four and thirty carbons.
- the hydrophobic region is a quaternary amine- containing moiety having a terminal hydrophobic substituent.
- Suitable hydrophobic regions which can include a hydrophobic moiety and/or a quaternary amine- containing moiety are described herein and in U.S. Patent Nos. 5,607,669, 5,679,717 and 5,618,530, the entire contents of which are incorporated herein by reference in their entirety.
- the polymers of the present invention offer desirable pharmacological properties such as excellent fat binding properties and low toxicity.
- undesirable side effects experienced, such as steatorrhea, when the lipase inhibitors are administered alone can be lessened.
- the invention relates to a method for treating obesity comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers.
- the fat- binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
- the invention in another aspect, relates to a method for reducing the abso ⁇ tion of dietary fat comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers.
- the fat-binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
- the invention relates to a method for treating hypertriglyceridemia in a mammal comprising the step of orally administering to a mammal a therapeutically effective amount of one or more fat-binding polymers.
- the fat-binding polymer is administered in combination with a therapeutically effective amount of a lipase inhibitor.
- a particular aspect of the invention relates to a method for treating steatorrhea comprising the step of orally administering to a mammal a therapeutically effective amount of a fat-binding polymer.
- the steatorrhea is a result of the administration of a lipase inhibitor.
- the invention also relates to fat-binding polymers useful in the method of the invention.
- "Lipases" as that term is used herein, are ubiquitous enzymes which hydrolyze ester bonds in neutral lipids. Examples of lipases include, but are not limited to, pancreatic and gastric lipases. The preferred substrates of lipases are insoluble in water. Lipases exhibit maximal activity in the presence of lipid/water interfaces. For example, pancreatic lipase, which is the key enzyme of dietary triglyceride abso ⁇ tion, exerts it activity at the water/lipid interface, in conjunction with bile salts and co-lipase.
- Lippase inhibitor refers to compounds which are capable of inhibiting the action of lipases, for example, gastric and pancreatic lipases.
- Lipstatin and its tetrahydro derivative, Tetrahydrolipstatin as described in U.S. Patent No. 4,598,089 to Hadvary et al, the entire content of which is hereby inco ⁇ orated by reference, are potent inhibitors of both gastric and pancreatic lipases, as well as cholesterol ester hydrolase.
- Lipstatin is a natural product of microbial origin, and tetrahydrolipstatin is the result of catalytic hydrogenation of lipstatin.
- Panclicins are analogues of Tetrahydrolipstatin (See e.g., Mutoh, M., et al., "Panclicins, Novel Pancreatic Lipase Inhibitors, II.
- Fat-binding polymers are polymers which absorb, bind or otherwise associate with fat thereby inhibiting (partially or completely) fat digestion, hydrolysis, or abso ⁇ tion in the gastrointestinal tract and/or facilitate the removal of fat from the body prior to digestion.
- the fat-binding polymers comprise one or more fat-binding regions.
- “Fat-binding regions”, as defined herein can include a positively charged region, a hydrophobic region, or a region which is both positively charged and hydrophobic.
- Fats are solids or liquid oils generally consisting of glycerol esters of fatty acids.
- Sources of fats include both animal and vegetable fats, for example, triglyceride esters of saturated and/or unsaturated fatty acids, free fatty acids, diglycerides, monoglycerides, phospholipids and cholesterol esters are fats, as defined herein.
- a variety of polymers can be employed in the invention described herein. The polymers are synthetic polymers which can be aliphatic, or aromatic. However, aliphatic and synthetic polymers are preferred.
- a "synthetic polymer”, as that term is employed herein, is a polymer which is not obtainable from a natural source either directly or through a minor derivatization of the naturally occurring form.
- the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic and/or hydrophilic monomers.
- Particularly preferred polymers comprise monomers having both cationic and hydroxy functional groups, and/or comprise a combination of separate monomers each having either a cationic or hydroxy functional group.
- Other preferred polymers comprise monomers having both cationic and hydrophobic groups, and/or comprise a combination of separate monomers each having either a cationic or a hydrophobic functional groups.
- the term "combination of monomers” or “combination of repeat units” means that at least one of each monomer or at least one of each repeat unit are present in the resulting polymerized polymer in any order.
- Many polymers can be conveniently manufactured from olefinic or ethylenic monomers (such as vinylalcohol, allylamine or acrylic acid) or condensation polymers. Examples of the preparation of preferred polymers of the invention are included in Examples 1-98.
- the polymers can include substituted or unsubstituted polyvinylalcohol, polyvinylamine, poly-N-alkylvinylamine, polyallylamine, poly-N- alkylallylamine, polydiallylamine, poly-N-alkyldiallylamine, polyalkylenimine, other polyamines, polyethers, polyamides, polyacrylic acids, polyalkylacrylates, polyacrylamides, polymethacrylic acids, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides, polystyrene, polyvinylnaphthalene, polyethylvinylbenzene, polyaminostyrene, polyvinylbiphenyl, polyvinylanisole, polyvinylimidazolyl, polyvinylpyridinyl, polydimethylaminomethylstyrene, polydiallylmethylammonimine,
- the polymers can be further characterized by one or more substituents such as substituted and unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups.
- substituents such as substituted and unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups.
- Suitable groups to employ include cationic or neutral groups, such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, ammonium groups, substituted or unsubstituted oxypolyethylene oxide, and mono, di or higher hydroxyalkyl groups .
- Particularly preferred polymers include substituted or unsubstituted polydiethylammonium chloride , polyvinylimidazole, polyalkylacrylates, polyacrylamides, polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides and copolymers thereof. These polymers can be further characterized by one or more substituents such as those discussed above.
- aliphatic amine polymers such as polyallylamine, polydiallylamine, polydiallylmethylamine, polyvinylamine, polyethylenimine.
- the amine polymer comprises one or more hydrophobic regions which are bound to a portion of the amine nitrogens of the amine polymer. In a particular embodiment, between about 1 and about 60 percent of the amine nitrogens are substituted, preferably between about 1 and about 30 percent.
- Additional particularly preferred polymers include maleic anhydride and maleic anhydride olefinic copolymers, itaconic anhydride, and amine derivatives thereof.
- the amine derivatives may preferably contain dimethyl amino groups.
- the hydrophobic region of the fat-binding polymer can include a hydrophobic moiety, for example, a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least four carbons.
- the hydrophobic moiety is an alkyl group of between about four and thirty carbons.
- the hydrophobic region is a quaternary amine- containing moiety having a terminal hydrophobic substituent.
- the fat-binding region comprises a nitrogen, for example, the nitrogen of an amine, capable of possessing a positive charge under conditions present in the gastro-intestinal tract.
- a nitrogen for example, the nitrogen of an amine, capable of possessing a positive charge under conditions present in the gastro-intestinal tract.
- a quaternary amine- containing moiety or the nitrogen of a polyamine.
- the fat-binding polymer is a hydroxyl-containing polymer, for example, poly(vinylalcohol) which can comprise further fat-binding regions.
- the polymer comprises a repeat unit having the formula -[CH 2 -CH-]
- R is a hydrophobic region.
- Preferred polymers are copolymers that comprise both cationic monomers such as those containing nitrogen, and monomers with hydroxy groups.
- Other polymers and methods of preparation, which can be used in the claimed invention have been reported in the patent literature in, for example, United States Patent Nos. 5,487,888, 5496,545, 5,607,669, 5,618,530, 5,624,963, 5,667,775, and 5,679,717 and co-pending U.S.
- the polymer can be linear or crosslinked.
- Crosslinking can be performed by reacting the copolymer with one or more crosslinking agents having two or more functional groups, such as electrophilic groups, which react with, for example, amine groups to form a covalent bond.
- Crosslinking in this case can occur, for example, via nucleophilic attack of the polymer amino groups on the electrophilic groups. This results in the formation of a bridging unit which links two or more amino nitrogen atoms from different polymer strands.
- Suitable crosslinking agents of this type include compounds having two or more groups selected from among acyl chloride, epoxide, and alkyl-X, wherein X is a suitable leaving group, such as a halo, tosyl or mesyl group.
- X is a suitable leaving group, such as a halo, tosyl or mesyl group.
- Examples of such compounds include, but are not limited to, epichlorohydrin, succinyl dichloride, acryloyl chloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, and dihaloalkanes.
- These crosslinking agents are referred to herein as multifunctional crosslinking agents.
- the polymer composition can also be crosslinked by including a multifunctional co-monomer as the crosslinking agent in the polymerization reaction mixture.
- a multifunctional co-monomer can be inco ⁇ orated into two or more growing polymer chains, thereby crosslinking the chains.
- Suitable multifunctional co-monomers include, but are not limited to, diacrylates, triacrylates, and tetraacrylates, dimethacrylates, diacrylamides, and dimethacrylamides.
- ethylene glycol diacrylate propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate.
- suitable multifunctional monomers include polyvinylarenes, such as divinylbenzene.
- the amount of cross-linking agent is typically between about 0.01 and about 10 weight % based on the combined weight of crosslinking agent and monomers, with 0.1-3% being preferred.
- the amount of cross-linking agent that is reacted with the polymer, when the crosslinking agent is a multifunctional agent, is sufficient to cause between about 0.1 and 6 percent of the nucleophiles present on the monomer, for example, an amine to react with the crosslinking agent.
- the hydrophobic region or regions of the fat-binding polymers include but are not limited to, for example, a hydrophobic moiety such as a substituted or unsubstituted, normal, branched or cyclic alkyl group having at least about four carbons and preferably at least 6 carbons.
- a hydrophobic moiety such as an alkyl group of at least four carbons and preferably at least 6 carbons can be bound to the fat-binding polymer, for example, through an amine of the fat-binding polymer.
- hydrophobic moiety is a moiety which, as a separate entity, is more soluble in octanol than water.
- the octyl group C 8 H 17
- the hydrophobic moieties can be a saturated or unsaturated, substituted or unsubstituted hydrocarbon group.
- Such groups include substituted and unsubstituted, normal, branched or cyclic alkyl groups having at least four carbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkyl groups and substituted or unsubstituted aryl or heteroaryl groups.
- the hydrophobic moiety includes an alkyl group of between about four and thirty carbons.
- hydrophobic moieties include the following alkyl groups n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-octadecyl, 2-ethylhexyl, 3-propyl-6-methyl decyl, phenyl and combinations thereof.
- Suitable hydrophobic moieties include haloalkyl groups of at least six carbons (e.g., 10-halodecyl), hydroxyalkyl groups of at least six carbons (e.g., 11-hydroxyundecyl), and aralkyl groups (e.g., benzyl).
- the positiviely charged region or regions of the fat binding polymers may include primary, secondary, tertiary or quaternary amines.
- the positively charged region or regions of the fat-binding polymers may include an amine nitrogen capable of possessing a positive charge under conditions present in the gastro-intestinal tract and a quaternary amine-containing moiety.
- Suitable quaternary amine-containing moieties used in conjunction with acrylate or acrylamide polymers include alkyl trialkylammonium groups also referred to as ammonioalkyl groups.
- alkyl trialkylammonium groups also referred to as ammonioalkyl groups.
- ammonioalkyl refers to an alkyl group which is substituted by a nitrogen bearing three additional substituents.
- the nitrogen atom is an ammonium nitrogen atom which bears an alkylene substituent, which links the ammonium nitrogen atom to the polymer, and three additional terminal alkyl substituents having from about one to about twenty- four carbons.
- a "terminal substituent" of the quaternary amine-containing moiety is any one of the three substituents on the quaternary amine nitrogen.
- the polymer is an amine polymer and the alkylene group links the ammonium nitrogen atom to the nitrogen atom of the polymer. It is to be understood that multiple moieties can be bound to the same amine and/or different amines of the polymer composition.
- the quaternary amine-containing moiety can bear at least one terminal hydrophobic alkyl substituent, such as an alkyl group having between about four and twenty- four carbons, thereby providing both a hydrophobic region and a positively charged region in combination.
- An ammonioalkyl group will further include a negatively charged counterion, such as a conjugate base of a pharmaceutically acceptable acid.
- Suitable counterions include CI “ , PO 4 " , Br “ , CH 3 SO 3 “ , HSO 4 “ , SO 4 2” , HCO 3 “ , CO 3 2” , acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, tartrate, polyacrylate, an amino acid derivative, and a nucleotide.
- Suitable ammonioalkyl groups are of the general formula:
- R 3 wherein, R 1 , R 2 and R 3 represent an alkyl group, wherein each R'-R 3 , independently, is a normal or branched, substituted or unsubstituted alkyl group having a carbon atom chain length of between about one to about twenty- four carbon atoms, n is an integer having a value of two or more and Y is a negatively charged counterion.
- R 1 , R 2 and R 3 are all methyl groups and n is an integer between about 2 and about 12.
- Examples of preferred alkylene linking groups are ethyl, propyl, butyl, pentyl, hexyl, octyl, and decyl groups.
- Example of suitable quaternary amine-containing moieties include, but are not limited to: 3-(trimethylammonio)propyl; 4-(trimethylammonio)butyl; 6-(trimethylammonio)hexyl ; 8-(trimethylammonio)octyl; 10-(trimethylammonio)decyl; 12-(trimethylammonio)dodecyl and combinations thereof.
- a particularly preferred amine-containing moiety is a 6-(trimethylammonio)hexyl group.
- quaternary amine-containing moiety and a hydrophobic moiety are present in the same substituent, thereby providing both a positively charged and hydrophobic region in combination.
- the quaternary amine nitrogen or ammonium nitrogen of the quaternary amine-containing moiety is bound to the polymer backbone by an alkylene having two or more carbons.
- at least one of the three terminal substituents (R 1 , R 2 and R 3 ) of the ammonium nitrogen is a hydrophobic alkyl group having from four to about twenty- four carbons.
- the remaining terminal substituents are each independently a normal or branched, substituted or unsubstituted alkyl group having from one to about twenty- four carbons or a hydrogen atom.
- at least two of the three terminal substituents can be hydrophobic alkyl groups having from four to about twenty-four carbons, the remainder having from one to about twenty-four carbons or a hydrogen atom.
- all three of the terminal substituents can be hydrophobic alkyl groups having from six to about twenty-four carbons.
- hydrophobic alkyl group includes a substituted or unsubstituted alkyl group having from four to about twenty- four carbons and which is hydrophobic, as earlier defined.
- the hydrophobic alkyl group can be, for example, a normal or branched, substituted or unsubstituted alkyl group having from six to about twenty-four carbons.
- quaternary amine-containing moieties which provide both a hydrophobic and quaternary amine-containing substituent, include, but are not limited to:
- quaternary amine-containing moieties include secondary and tertiary analogs, such as 4-(dioctylmethylammonio)4-methylbutyl and 4- (dioctylmethylammonio)-4,4-dimethylbutyl.
- the fat-binding polymers of the invention can be formed, for example, by reacting a polymer, which can be linear or crosslinked, with a suitable alkylating agent or by polymerizing an alkylated monomer.
- a suitable alkylating agent as that term is employed herein, means a reactant that, when reacted with a monomer or a copolymer characterized by a repeat unit of the invention and having a nucleophilic site capable of reaction with the alkylating agent, causes a hydrophobic substituent, as described herein, to be covalently bound to one or more of sites on the fat-binding polymer, for example, the amine nitrogen atoms or hydroxyl oxygens of an amine-containing or hydroxyl-containing monomer or polymer, respectively.
- substituents when multiple substituents are employed, they can be bound to the same and/or different nucleophilic sites of the fat-binding polymer, for example, the same and/or different amine nitrogens of an amine-containing fat-binding polymer or hydroxyl oxygen of a hydroxyl-containing polymer.
- Suitable alkylating agents are compounds comprising an alkyl group or alkyl derivative, having at least four carbon atoms, which is bonded to a leaving group such as a halo (e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy group).
- a halo e.g., chloro, bromo or iodo
- tosylate mesylate or epoxy group
- alkyl halides having at least four carbon atoms such as n-hexyl halide,n- heptyl halide, n-octyl halide, n-nonyl halide, n-decyl halide, n-undecyl halide, n- dodecyl halide, n-tetradecyl hal
- a dihaloalkane that includes an alkyl group of at least four carbons (e.g., a 1,10-dihalodecane); a hydroxyalkyl halide having at least four carbon atoms (e.g., an 11-halo-l-undecanol); an aralkyl halide (e.g., a benzyl halide); an alkyl epoxy ammonium salt having at least six carbons (e.g., glycidylpropyl-trimethylammonium salts) and epoxyalkylamides having at least six carbons (e.g., N-(2,3-epoxypropyl) butyramide or N-(2,3-epoxypropyl) hexanamide).
- a dihaloalkane that includes an alkyl group of at least four carbons (e.g., a 1,10-dihalodecane); a hydroxyalkyl halide having at least four
- Preferred halogen components of the alkyl halides are bromine and chlorine.
- Particularly preferred alkylating agents which, when reacted with the polymer composition, will cause formation of an amine polymer reaction product that includes a first substituent, are 1-bromodecane and 1-chlorooctane.
- alkylating agents which can provide a quaternary amine-containing moiety have the general formula:
- R 1 , R 2 , and R 3 represent an alkyl group, wherein each R independently is a normal or branched, substituted or unsubstituted alkyl group having a carbon atom chain length of between about one to about twenty four carbon atoms, n is an integer having a value of two or more, X is a leaving group as earlier described, and
- Y is a negatively charged counterion.
- the alkylating agent When at least one of the three terminal substituents of the quaternary amine alkylating agent is a hydrophobic alkyl group having from four to about twenty- four carbons, the alkylating agent therefore provides both a hydrophobic moiety and a quaternary amine-containing moiety.
- the alkylene group in this instance is three or more carbon atoms in length.
- quaternary ammonium compounds suitable as alkylating agents include the following: (4-bromobutyl)dioctylmethylammonium bromide;
- suitable alkylating agents include secondary and tertiary analogs, such as (3-bromobutyl)dioctylmethylammonium bromide and (3 -chloro-3, 3 -dimethyl propyl)dioctylmethylammonium bromide.
- suitable alkyl trimethylammonium alkylating agents include alkyl halide trimethylammonium salts, such as:
- the fat-binding polymers of the invention can be formed, for example, by reacting a polymer, which can be linear or crosslinked, with a suitable modifying agent.
- a "modifying agent”, as that term is employed herein, means a reactant that, when reacted with a monomer or a copolymer characterized by a repeat unit of the invention and having a nucleophilic site capable of reaction with the modifying agent, causes a hydrophobic substituent, as described herein, to be covalently bound to one or more of sites on the fat-binding polymer, for example, the amine nitrogen atoms of an amine-containing polymer. Further, when multiple substituents are employed, they can be bound to the same and/or different nucleophilic sites of the fat-binding polymer, for example, the same and/or different amine nitrogens of an amine-containing fat-binding polymer.
- Suitable modifying agents are compounds comprising substituted alkyl group or alkyl aromatic groups which is bonded to a leaving group such as a halo (e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy group).
- a halo e.g., chloro, bromo or iodo
- tosylate mesylate or epoxy group.
- Suitable modifying agents which provide a hydrophilic moiety include haloalkanols, (for example, 2-bromoethanol, 3-bromopropanol, 4-bromobutanol, 4-chlorobutanol and 3-bromo-2-hydroxy propanol), haloalkanoic acids (for example chloracetic acid, bromoacetic acid, 3-bromo propionic acid and 4-bromobutyric acid, glycidol, glycidyl trimethylammonium chloride, and ethylene oxide.
- compositions comprising at least one repeat unit or a combination of repeat units selected from the following group of repeat unit formulas, or combinations of repeat unit formulas.
- Rl H, or CH 3
- R2 H, or CH 3
- R5 H, or an alkyl chain from C, to C 22
- m 0 - 4
- p 5 - 125
- Rl H, or CH 3
- R2 H, or CH 3
- R4 a hydrophobic group
- R5 H, or an alkyl chain from C, to C 22
- Rl H, or CH 3
- R2 H, or CH 3
- R3 H, or CH 3
- R4 a hydrophobic group
- m 0 - 4
- Rl H, or CH 3
- R2 H, or CH 3
- R3 H, or CH 3
- R4 a hydrophobic group
- R5 an alkyl chain from C, to C 22
- m 0 - 4
- R5 H, or an alkyl chain from C, to C '22 (v ⁇ i)
- R5 H, or an alkyl chain from C, to C 22
- R6 H
- R7 H
- R8 H
- R5 H, or an alkyl chain from C, to C 22 ,
- such polymer contains 11 wt% of the PEG-containing monomer;
- polymer of Formula VI which may be expressed as Poly(N,N-diallyl-N,N- di(2,3-dihydroxypropyl)ammonium chloride);
- Another particularly preferred polymer of the invention may be expressed as Polyethyleneimine 80% ethoxylated, the structure of which is understood in the art.
- the fat-binding polymer can have a lipase inhibitor covalently bound to the polymer as described in PCT/US99/00195.
- the fat-binding polymer can be administered in combination with a lipase inhibitor which is convalently bound to a polymer as described in PCT/US99/00195, the entire content of which is inco ⁇ orated herein by reference.
- the terms “therapeutically effective amount” and “therapeutic amount” are synonymous.
- the terms refer to an amount which is sufficient to treat obesity, reduce the abso ⁇ tion of fat or treat hypertriglyceridemia.
- the dosage of fat-binding polymer administered to the patient will vary depending among other things on the weight of the patient and the general health of the patient. The dosage can be determined with regard to established medical practice.
- the amount of fat- binding polymer administered can be in the range of from about 0.01 mg/kg of body weight/day to about lg/kg of body weight/day.
- the amount of lipase inhibitor which can be administered in combination with the fat-binding polymers of the invention can be determined with regard to accepted medical practice (e.g. the Physicians Desk Reference).
- the preferred and particularly preferred fat-binding polymers in accordance with the invention are administered in combination with a lipase inhibitor, as described herein.
- the term "in combination" in this context includes both simultaneous or sequential administration (either type of compound first) of the fat-binding polymer and lipase inhibitor.
- the fat-binding polymer and lipase inhibitor when used in combination, can be employed together in the same dosage form or in separate dosage forms taken at the same time or within a time period, wherein both the fat-binding polymer and lipase inhibitor are present in a therapeutically effective amount.
- the fat-binding polymers of the invention can be formulated using conventional inert pharmaceutical adjuvant materials into dosage forms which are suitable for oral administration.
- the oral dosage forms include tablets, capsules, suspension, solutions, and the like.
- the identity of the inert adjuvant materials which are used in formulating the fat-binding polymers of the invention will be immediately apparent to persons skilled in the art.
- These adjuvant materials include, for example, gelatin, albumin, lactose, starch, magnesium stearate, preservatives (stabilizers), melting agents, emulsifying agents, salts, and buffers.
- a 250-mL round-bottomed flask was fitted with an overhead stirrer, a reflux condenser, and a thermocouple probe.
- the following materials were placed into the flask in the order specified: a solution of decylacrylamide (2.83 g, 0.0134 mole) in tert-butanol (45 mL), 3-acrylamidopropyltrimethylammonium chloride (18.45 g of a 75 percent solution in water, 0.067 mole), deionized water (40 mL), and acrylamide (13.33 g, 0.1875 mole).
- the resulting mixture was stirred and heated to 50 °C. A clear, slightly yellow solution resulted.
- the solution was sparged for at least 30 minutes with a vigorous nitrogen flow from an 18-gauge syringe needle whose tip was placed below the surface of the stirring solution.
- the radical initiator 2,2'azobis(2-amidinopropane) dihydrochloride (0.363 g, 0.00134 mole) was then added to the solution and the temperature was increased to 60 °C.
- the solution was stirred at 60 °C for 14-16 hours.
- the solution was then cooled to room temperature and poured into 3 L of isopropanol, resulting in precipitation of the polymeric product as a colorless solid. This mixture was stirred for 1-3 hours, and the isopropanol was decanted away from the polymer product.
- a fresh 3-L portion of isopropanol was then added, and the mixture was stirred for 3-6 hours. Again, the isopropanol was decanted away, and another 3-L portion of fresh isopropanol was added to the polymer. The mixture was stirred for 6-14 hours and the isopropanol was decanted away from the polymer product.
- the polymer was placed on a glass tray, and dried in a forced-air oven at 70 °C for 24-48 hours. The dried solid was then ground to a fine powder using a commercial coffee grinder. The fine powder was placed into a glass tray in a forced air oven at 70 °C for at least 24 hours. A colorless solid (30.04 g) was obtained.
- Example 4 Poly((3-acrylamidopropyI)trimethylammonium chloride-co- acrylamide-co-N,N-didecylacrylamide) Mol% monomer composition: 25/70/5
- the procedure of example 1 was followed substituting the following materials and amounts: didecylacrylamide (3.69 g, 0.0105 mole) in tert-butanol (37 mL), 3-acrylamidopropyltrimethylammonium chloride (14.48 g of a 75 percent solution in water, 0.053 mole), deionized water (34.4 mL), acrylamide (10.15 g, 0.147 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (0.285 g, 0.00105 mole). The amount of polymer obtained was 23.62 g.
- Example 9 PoIy(2-(Methacryloyloxy)ethyl-tert-butylamine hydrochloride) The procedure of example 1 was followed using the following reagents:
- example 1 The procedure of example 1 was followed using the following reagents: styrene (5.03 g, 0.048 mole) in ethanol (80 mL), 3-acrylamidopropyltrimethyl- ammonium chloride (19.96 g of a 75 percent solution in water, 0.072 mole), 2,2'- azobisisobutyronitrile (0.198 g, 0.0012 mole).
- the solvent used for precipitation and washing of the polymer was acetone.
- the amount of polymer obtained was 14.5 g.
- Example 13 Poly((3-acrylamidopropyl)trimethylammonium chloride-co- acrylamide-co-N-phenylacrylamide) Mol% monomer composition: 25/70/5
- the procedure of example 1 was followed substituting the following materials and amounts: phenylacrylamide (33.82 g, 0.230 mole) in tert-butanol (1000 g), 3-acrylamidopropyltrimethylammonium chloride (316.7 g of a 75 percent solution in water, 1.149 mole), deionized water (921 mL), acrylamide (228.67 g, 3.217 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (3.323 g, 0.0230 mole) in deionized water (24 g).
- the amount of polymer obtained was 532 g.
- a 5000-mL round-bottomed flask was fitted with an overhead stirrer, a reflux condenser, and a thermocouple probe.
- the following materials were placed into the flask in the order specified: 3-acrylamidopropyltrimethylammonium chloride (396.86 g of a 75 percent solution in water, 1.44 mole), deionized water (1500 mL), and acrylamide (102.35 g, 1.44 mole).
- the resulting mixture was stirred at approximately 23 °C. A clear, slightly yellow solution resulted.
- the solution was sparged for at least 60 minutes with a vigorous nitrogen flow from an 18-gauge syringe needle whose tip was placed below the surface of the stirring solution.
- Potassium metabisulfite (0.213 g, 0.00096 mole) and potassium persulfate (0.259, 0.00096 mole) were then each separately dissolved in a small amount of water and added individually to the solution. After 2-10 minutes, the temperature was increased to 60 °C. The solution was stirred at 60 °C for 5-6 hours. The flask was then fitted with a distillation head and the solution was heated to 95 °C. The vigorous nitrogen flow was resumed and 500 mL of water was distilled out of the flask in order to facilitate the work-up procedure. The polymer solution was cooled and poured into 22 L of isopropanol, resulting in precipitation of the polymeric product as a colorless solid.
- Example 17 Poly((3-acryIamidopropyl)trimethylammonium chloride) The procedure of example 16 was followed using the following reagents: 3- acrylamidopropyltrimethylammonium chloride (533.3 g of a 75 percent solution in water, 1.94 mole), deionized water (1467 mL), potassium metabisulfite (0.143 g, 0.00065 mole) and potassium persulfate (0.174, 0.00065 mole). The amount of polymer obtained was 372 g.
- a 1000-mL round-bottomed flask was fitted with an overhead stirrer, a reflux condenser, and a thermocouple probe.
- the following materials were placed into the flask in the order specified: 3-acrylamidopropyltrimethylammonium chloride (141.04 g of a 75 percent solution in water, 0.512 mole), deionized water (511 mL), and N-vinyl-2-pyrrolidinone (14.22 g, 0.128 mole).
- the resulting mixture was stirred at approximately 23 °C.
- a clear, slightly yellow solution resulted.
- the solution was sparged for at least 60 minutes with a vigorous nitrogen flow from an 18-gauge syringe needle whose tip was placed below the surface of the stirring solution.
- the solution was then cooled to room temperature and poured into 3 L of isopropanol, resulting in precipitation of the polymeric product as a colorless solid. This mixture was stirred overnight, and the isopropanol was decanted away from the polymer product. A fresh 3-L portion of isopropanol was then added, and the mixture was stirred for 6-8 hours. Again, the isopropanol was decanted away.
- the polymer was placed on a glass tray, and dried in a forced-air oven at 70 °C for 24-48 hours. The dried solid was then ground to a fine powder using a commercial coffee grinder. The fine powder was placed into a glass tray in a forced air oven at 70 °C for at least 24 hours. A colorless solid (15.5 g) was obtained.
- Example 20 Poly(diallyldimethylammonium chloride-co-acrylic acid) Monomer mole ratio: 90/10
- the procedure of example 19 was followed using the following reagents: diallyldimethylammomum chloride (1465.9 g of a 65 percent solution in water, 5.89 mole), deionized water (3486.9 mL), acrylic acid (47.19 g, 0.655 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (8.88 g, 0.0327 mole).
- the amount of polymer obtained was 632 g.
- Example 21 Poly((3-acrylamidopropyl)trimethylammonium chloride-co-O- acryloyl-O'-methylpolyethylene glycol 5,000) Wt% monomer composition: 89/11
- Example 22 Poly(3-methyl-l-vinylimidazolium chloride-co-acrylamide) Monomer mole ratio: 50/50
- a 50-mL round-bottomed flask was fitted with a magnetic stirrer, a reflux condenser, and a thermocouple probe.
- the following materials were placed into the flask in the order specified: N,N-diallyl-2-hydroxyethylamine (10 g), concentrated HCl (7 g), deionized water (3 mL).
- the solution was degassed for 30 minutes by bubbling with nitrogen from an 18-gauge needle.
- 2,2'Azobis(2-amidinopropane) dihydrochloride (0.095 g, 0.00035 mole) was then added and the solution was heated to 60 °C. The solution was stirred at 60 °C overnight.
- the solution was then cooled to room temperature and poured into 1 L of isopropanol, resulting in precipitation of the polymeric product as a colorless solid.
- This mixture was stirred for 1 -3 hours, and the isopropanol was decanted away from the polymer product.
- a fresh 1-L portion of isopropanol was then added, and the mixture was stirred for 3-6 hours. Again, the isopropanol was decanted away, and another 1-L portion of fresh isopropanol was added to the polymer.
- the mixture was stirred overnight and the isopropanol was decanted away from the polymer product.
- the polymer was placed on a glass tray, and dried in a forced-air oven at 70 °C for 24-48 hours. The dried solid was then ground to a fine powder using a commercial coffee grinder. The fine powder was placed into a glass tray in a forced air oven at 70 °C for at least 24 hours. A colorless solid (8 g) was obtained.
- a 250-mL flask was equipped with an overhead mechanical stirrer, condenser and a thermocouple probe.
- the following materials were placed into the flask in the order specified: poly(2-ethyl-2-oxazoline) (25 g), deionized water (95 mL), concentrated HCl (9.8 g).
- the solution was heated to reflux with stirring for 8 hours.
- the solution was then poured into 1.5 L of acetone resulting in the precipitation of the polymeric product.
- the mixture was sti ⁇ ed for 1 hour.
- the acetone was then decanted away and a fresh 1.5-L portion of acetone was added. After 2 hours of stirring, the acetone was decanted away, and the solid was blended in a commercial blender containing fresh acetone.
- the solid was collected by filtration and suspended in fresh acetone overnight. The solid was then collected and placed on a glass tray, and dried in a forced-air oven at 70 °C for 24-48 hours. The dried solid was then ground to a fine powder using a commercial coffee grinder. The fine powder was placed into a glass tray in a forced air oven at 70 °C for at least 24 hours. A colorless solid (30.04 g) was obtained.
- Poly(allylamine) HCl (60g of 50 percent aqueous solution, 0.321 mole monomer equivalents) was dissolved in 80 mL of water and was then heated to 50 °C in a 500-mL flask equipped with an overhead mechanical stirrer, condenser and a thermocouple probe. The pH of the solution was adjusted to 10 by the addition of NaOH (50 percent solution). Glycidol (23.77g 0.321 mol) was added slowly to the stirred solution. A large exotherm was observed during the addition of the glycidol. This mixture was then heated at 50 °C for 3 hours giving a very viscous solution.
- the reaction mixture was cooled and then poured into a dialysis bag (Spectra/Por; molecular weight cut off 6000-8000) and dialyzed against 19 liters of deionized water.
- the dialysis solution was changed until a conductivity of ⁇ 1 mS/cm was recorded.
- the contents of the dialysis bag were then placed in a beaker and the pH of the solution adjusted to a value ⁇ 2 with concentrated HCl.
- This solution was then transferred to drying trays and placed in a convection oven at 70 °C for 24 hours.
- the dried solid was ground to a fine powder using a lab mill and then passed through a sieve (80 mesh).
- Example 28 Modification of polyallylamine) HCl with 200 mol % Glycidol
- Example 27 The procedure of example 27 was followed using the following materials: Poly(allylamine) HCl (60g of 50 percent aqueous solution, 0.321 mole monomer equivalents), deionized water (80 mL), glycidol (47.54 g, 0.642 mole). The amount of polymer obtained was 66.8 g.
- Example 29 Modification of polyallylamine) HCl with 300 mol % Glycidol
- Example 27 The procedure of example 27 was followed using the following materials: Poly(allylamine) HCl (40g of 50 percent aqueous solution, 0.214 mole monomer equivalents), deionized water (80 mL), glycidol (47.54 g, 0.642 mole). The amount of polymer obtained was 48.9 g.
- Example 27 The procedure of example 27 was followed using the following materials: Poly(diallylamine) HCl (106.8 g of 28.1 percent aqueous solution, 0.225 mole monomer equivalents), deionized water (43.2 mL), glycidol (41.57 g, 0.561 mole). The amount of polymer obtained was 56.3 g.
- Example 31 40 Mol% modification of poly(diallylmethylamine) HCl with 2- chloroaceticic acid
- poly(diallylmethylamine), 120 g of a 44.22 percent aqueous solution 0.359 mole monomer equivalents
- poly(diallylmethylamine) 120 g was dissolved in 60 mL of deionized water and 225 mL ethanol.
- the solution was heated to 70 °C.
- the pH of the solution was adjusted to 10 by the addition of NaOH (50 percent solution).
- 2-Chloroacetic acid 13.58 g, 0.144 mole was then added in one portion.
- the reaction mixture was sti ⁇ ed at 70°C for 16-18 hours.
- the pH of the solution was checked periodically during this time and was maintained at 10 by the addition of 50 percent NaOH.
- the solution was then cooled to room temperature, transferred to a dialysis bag (Spectra/Por molecular weight cut off 6000-8000) and dialyzed against 19 liters of deionized water.
- the dialysis solution was changed until a conductivity of ⁇ lmS/cm was recorded.
- the contents of the dialysis bag was then placed in a beaker and the pH of the solution adjusted to a value ⁇ 2 with concentrated HCl.
- Example 32 30 Mol% modification of poly(diallylmethylamine) HCl with 2- chloroaceticic acid
- the procedure of example 31 was followed using the following materials: poly(diallylmethylamine) HCl (120 g of 44.22 percent aqueous solution, 0.359 mole monomer equivalents), deionized water (60 mL), ethanol (225 mL), 2-chloroacetic acid (10.19 g, 0.108 mole). The amount of polymer obtained was 53.8 g.
- Example 33 20 Mol% modification of poly(diallylmethylamine) HCl with 2- chloroaceticic acid
- poly(diallylmethylamine), (67.84 g of a 44.22 percent aqueous solution 0.203 mole monomer equivalents) was dissolved in 60 mL of deionized water and 120 mL ethanol.
- the solution was heated to 70 °C.
- the pH of the solution was adjusted to 10 by the addition of NaOH (50 percent solution).
- 3- Bromopropionic acid (32.63 g, 0.213 mole) was then added in one portion.
- the reaction mixture was stirred at 70 °C for 16-18 hours.
- the pH of the solution was checked periodically during this time and was maintained at 10 by the addition of 50 percent NaOH.
- the solution was then cooled to room temperature, transferred to a dialysis bag (Spectra/Por molecular weight cut off 6000-8000) and dialyzed against 19 liters of deionized water.
- the dialysis solution was changed until a conductivity of ⁇ lmS/cm was recorded.
- the contents of the dialysis bag was then placed in a beaker and the pH of the solution adjusted to a value ⁇ 2 with concentrated HCl.
- This solution was then transferred to drying trays and placed in a convection oven at 70 °C for 24 hours.
- the dried solid was ground to a fine powder using a lab mill and then passed through a sieve (80 mesh).
- the product was then replaced in a convection oven at 70 °C for 48 hours to remove any residual solvent.
- the amount of polymer obtained was 35 g.
- example 34 The procedure of example 34 was followed using the following materials: poly(allylamine) HCl (40 g of a 50 percent aqueous solution, 0.214 mole monomer equivalents), deionized water (50 mL), 3-bromopropionic acid (34.36 g, 0.225 mole). The amount of polymer obtained was 28.5 g.
- Example 34 The procedure of example 34 was followed using the following materials: polyethylenimine (30 g of a 50 percent aqueous solution, 0.348 mole monomer equivalents), deionized water (45 mL), 3-bromopropionic acid (55.9 g, 0.365 mole). The amount of polymer obtained was 37.3 g.
- Example 39 Polydiallylamine hydrochloride
- Diallylamine (2000.3 g) was added slowly over a period of 2 days to concentrated HCl (2035.6 g). The temperature of the reaction was maintained below 10 ° C by cooling the flask in an ice-salt-water bath, and by adjusting the addition rate. The room temperature pH of the resulting diallylamine hydrochloride solution (68.16 percent diallylamine hydrochloride) was 0.005.
- diallylamine hydrochloride 3667.8 g of a 68.16 percent solution
- deionized water 4665.5 g
- the resulting solution had pH 0.74.
- NaOH 66.8 g of a 50 percent aqueous solution
- the resulting solution had pH 2.55.
- Nitrogen gas was bubbled through the solution, via a stainless steel needle, with stirring, and venting on top of the air condenser for 2 hours. The nitrogen line was put on top of the air condenser with positive pressure from a mineral oil bubbler.
- reaction solution was allowed to cool down slowly to 49 °C, and to the flask was added 125.0 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized water.
- the solution was heated to 60 "C over a period of about 15 minutes, with a heating mantle connected to a J-Kem temperature controller.
- the solution was heated at 60 °C for 18 hours.
- the reaction temperature rose to 62 °C, and slowly cooled back down to 60 °C over a 1 hour period.
- reaction solution was allowed to cool down slowly to 40 °C, and to the flask was added 125.0 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized water.
- the solution was heated to 60 °C over a period of about 15 minutes, with a heating mantle connected to a J-Kem temperature controller.
- the solution was heated at 60 °C for 18 hours.
- the reaction temperature rose to 63 ° C, and slowly cooled back down to 60 °C over a 1 hour period. After cooling to room temperature, the solution was a dark orange viscous, flowable, clear solution.
- the flask contents were combined with deionized water (4166.7 g).
- the resulting solution had pH 4.41.
- SEC analysis Mw 61,500 Daltons; polydispersity 2.43.
- Diallylmethylamine (361.0 g) was added slowly over a period of 2 hours, 10 minutes to concentrated HCl (320.3 g). The temperature of the reaction was maintained below 10 °C by cooling the flask in an ice-salt-water bath, and by adjusting the addition rate.
- the room temperature pH of the resulting diallylmethylamine hydrochloride solution was 6.492, and the solution had two phases, a small oil phase (top) with a large aqueous phase (bottom).
- concentrated HCl (22.6 g)
- the final solution was a single phase, and contains 68.04 percent diallylmethylamine hydrochloride by weight.
- diallylmethylamine hydrochloride 73.5 g of a 68.04 percent solution
- deionized water 26.5 g
- the resulting solution had pH 0.871.
- To the flask was added 50 percent aqueous NaOH until the resulting solution had pH 2.53. Nitrogen gas was bubbled through the solution, via a stainless steel needle, with stirring, and venting on top of the vigreux column for 30 minutes The nitrogen line was put on top of the vigreux column with positive pressure from a mineral oil bubbler.
- reaction solution was allowed to cool down slowly to room temperature, and to the flask was added 2.5 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized water.
- the reaction solution was heated to 60 °C over a period of about 30 minutes.
- the reaction solution was heated at 60 °C for another 18 hours.
- the reaction solution was allowed to cool down slowly to room temperature, and to the flask was added 2.5 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized water.
- the reaction solution was heated to 60 °C over a period of about 30 minutes.
- reaction solution was heated at 60 ° C for another 18 hours. After cooling to room temperature, the reaction solution was a clear dark orange, viscous and flowable solution. The flask contents were combined with deionized water (150.0 g). The resulting solution had pH 4.36. SEC analysis: Mw 54,100 Daltons; polydispersity 2.13.
- Example 41 Functionalization of poly(ethy!ene-alt-maleic anhydride) with 3- (dimethylamino)propylamine.
- poly(ethylene-alt-maleic anhydride) (20.0 g) in N,N- dimethylformamide (180 mL) under a nitrogen atmosphere was added 3- (dimethylamino)propylamine (40 mL).
- the mixture was heated at 60 °C overnight and allowed to cool to room temperature.
- Concentrated HCl (47 g) was added and the mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C for 48 hours to afford 37.8 g.
- Example 43 Functionalization of poly(diallylmethylamine) with polyoxyethylene(40) nonylphenyl glycidyl ether.
- Polyoxyethylene(40) nonylphenyl glycidyl ether was synthesized by reacting polyoxyethylene(40) nonylphenyl ether (100.0 g) with epichlorohydrin (60 mL) in the presence of deionized water (0.750 g), NaOH (6 g), and 3,5-di-tert-butyl-4- hydroxyanisole (0.23 g) at 60 °C for 10 hours. After cooling to room temperature, methylene chloride (200 mL) was added, and this solution was extracted with a solution of deionized water (200 mL) and potassium dihydrogen phosphate (10 g).
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (677 g of a 44.22 percent aqueous solution), deionized water (823 g) and NaOH (87 g of a 50 percent aqueous solution) overnight.
- polydiallylmethylamine basic solution 158.9.0 g
- polyoxyethylene(40) nonylphenyl glycidyl ether 3.0 g
- concentrated HCl 25.0 g
- the reaction mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C for 48 hours to afford 31.5 g.
- Example 44 Functionalization of poly(diallylmethylamine) with polyoxyethylene(40) nonylphenyl glycidyl ether.
- polydiallylmethylamine basic solution 158.7 g; Example 43
- polyoxyethylene(40) nonylphenyl glycidyl ether 6.0 g; Example 43
- concentrated HCl (18.0 g) was added.
- the reaction mixture was transferred to a Spectra Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 33.4 g.
- Example 45 Functionalization of poly(diallylmethylamine) with polyoxyethylene(40) nonylphenyl glycidyl ether.
- polydiallylmethylamine basic solution 158.7 g; Example 43
- polyoxyethylene(40) nonylphenyl glycidyl ether 9.0 g; Example 43.
- concentrated HCl 32.6 g
- the reaction mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 37.3 g.
- Example 46 Functionalization of poly(diallylmethylamine) with polyoxyethylene(40) nonylphenyl glycidyl ether.
- Example 47 Functionalization of poly(diallylmethylamine) with polyoxyethylene(40) nonylphenyl glycidyl ether.
- polydiallylmethylamine basic solution 158.7 g; Example 43
- polyoxyethylene(40) nonylphenyl glycidyl ether 30 g; Example 43.
- concentrated HCl was added until the pH of the resulting solution was less than 1.0.
- the reaction mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 60.0 g.
- Example 49 Functionalization of poly(diallylmethylamine) with polyoxyethylene(23) lauryl glycidyl ether.
- Polyoxyethylene (23) lauryl glycidyl ether was synthesized by reacting polyoxyethylene (23) lauryl ether (50.0 g) with epichlorohydrin (50 mL) in the presence of deionized water (0.625 g), NaOH (5 g), and 3,5-di-tert-butyl-4- hydroxyanisole (0.28 g) at 60 °C for 10 hours. After cooling to room temperature, methylene chloride (100 mL) was added, and this solution was extracted with a solution of deionized water (100 mL) and potassium dihydrogen phosphate (5 g).
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (677 g of a 44.22 percent aqueous solution), deionized water (823 g) and NaOH (87 g of a 50 percent aqueous solution) overnight. To a portion of the polydiallylmethylamine basic solution (158.7 g) was added polyoxyethylene(23) lauryl glycidyl ether (3.0 g).
- Example 50 Functionalization of poly(diallylmethylamine) with polyoxyethylene(23) lauryl glycidyl ether.
- Example 51 Functionalization of poly(diallylmethylamine) with glycidol.
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous solution) overnight.
- polydiallylmethylamine hydrochloride 615.4 g of a 44.22 percent aqueous solution
- deionized water 745.2 g
- NaOH 7.8 g of a 50 percent aqueous solution
- the reaction mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution
- Example 52 Functionalization of poly(diallylmethylamine) with glycidol.
- Example 54 Polyethylenimine, 80% ethoxylated. A solution of polyethylenimine, 80 percent ethoxylated (269.1 g of a 35-40 percent solution in water; Aldrich Chemical Company) was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours. The dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford the desired compound.
- Example 55 Copoly(N-[3-(dimethylamino)propyl]acrylamide/acrylamide N- dodecylacrylamide) (48:48:5).
- the solution was decanted from the precipitated polymer.
- the polymer was suspended in isopropanol (500 mL), stirred for at least 15 minutes, and allowed to settle. After decanting, the polymer was similarly washed an additional 3 times with isopropanol. The washed polymer was dried in a forced-air oven at 70 °C to afford 81.1 g.
- Example 56 Copoly(N-[3-(dimethylamino)propyl]acrylamide/acrylamide) (50/50).
- the solution was decanted from the precipitated polymer.
- the polymer was suspended in isopropanol (500 mL), stirred for at least 15 minutes, and allowed to settle. After decanting, the polymer was similarly washed an additional 3 times with isopropanol. The washed polymer was dried in a forced-air oven at 70 °C to afford 34.7 g.
- Example 58 Functionalization of polydiallylamine with (6-bromohexyl) trimethylammonium bromide.
- a solution of polydiallylamine hydrochloride (106.8 g of a 28.09 percent aqueous solution), deionized water (400 g), NaOH (9.6 g of a 50 percent aqueous solution), and (6-bromohexyl) trimethylammonium bromide (51.1 g) was heated to 60 °C for 18 hours. After 1 hour at 60 °C, NaOH (4.5 g of a 50 percent aqueous solution) was added. After 1.5 hours at 60 °C, NaOH (4.5 g of a 50 percent aqueous solution) was added. After 2 hours at 60 °C, NaOH (4.5 g of a 50 percent aqueous solution) was added.
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous solution) overnight. To a portion of the polydiallylmethylamine basic solution (158.6 g) was added poly(ethylene glycol) diglycidyl ether (9.0 g, Average Mn ca. 526, from Aldrich Chemical Co.). After stirring overnight, concentrated HCl (10 mL) was added.
- the reaction mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 9.3 g.
- Example 60 Poly[bis(2-chloroethyl)ether-alt-l,3-bis[3-(dimethylamino) propyl]urea], quaternized.
- a solution of poly[bis(2-chloroethyl)ether-alt-l ,3-bis[3-(dimethylamino) propyljurea], quaternized 566.7 g of a 62 percent solution in water; from Aldrich Chemical Co.
- quaternized 566.7 g of a 62 percent solution in water; from Aldrich Chemical Co.
- Spectra/Por 1 dialysis membrane bag molecular weight cutoff 6000 to 8000
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford the desired compound.
- Example 61 Functionalization of polyethylenimine with glycidol.
- a solution of polyethylenimine (60.0 g), deionized water (240 g), and 2- bromoethanol (49.4 mL) was heated at 50 °C under a nitrogen atmosphere for 18 hours. After 1.5 hours at 50 °C, NaOH (31.9 g of a 50 percent aqueous solution) was added. After cooling to room temperature, concentrated HCl (30 mL) was added. The reaction mixture was transferred to a Spectra Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours. The dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford the desired compound.
- Example 63 Protonation of polydiallylmethylamine with L-tartaric acid.
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous solution) overnight.
- Example 64 Polydiallyldimethyiammonium chloride.
- Polydiallyldimethyiammonium chloride (526.8 g of a 20 percent aqueous solution, average MW 200,000-350,000, from Aldrich Chemical Co.) was poured into isopropanol (12 L) and stirred for at least 15 minutes. The solution was decanted from the precipitated polymer. The washed polymer was dried in a forced- air oven at 70 °C to afford 90.8 g.
- Example 65 Functionalization of poly(diallylmethylamine) with polyoxyethylene(2,000) methyl glycidyl ether.
- NaH (3.28 g; 60 percent in oil from VWR) was weighed out in a three- necked 1-L round-bottomed flask and washed 3 times with 200 mL of hexane. The hexane was removed and the NaH was suspended in 350 mL of anhydrous dioxane.
- Polyoxyethylene(2,000) methyl glycidyl ether 130 g; average Mn 2,000, obtained from Aldrich Chemical Co.
- the reaction mixture was heated to 45 °C and then 12.03 g of epichlorohydrin was added to this solution and the reaction mixture was heated overnight.
- the reaction was allowed to cool to room temperature and was then filtered.
- the filtered solution was concentrated using a rotary evaporator to give a white solid.
- the solid was dissolved in 500 mL of methylene chloride and the polymer was precipitated in 4 L of diethyl ether.
- the polymer was dissolved in 500 mL of methylene chloride and the polymer was precipitated in 4 L of diethyl ether and filtered.
- the polymer was dried in a vacuum oven at room temperature over 72 hours to afford 110.9 g of polyoxyethylene (2,000) methyl glycidyl ether.
- Example 67 Functionalization of poly(diallylmethylamine) with polyoxyethylene(2,000) methyl glycidyl ether
- Example 68 Copoly(diallylmethylamine/acrylamide) (50:50).
- a solution of diallylmethylammonium chloride was prepared by adding diallylmethylamine (250 g) dropwise to a solution that was cooled in an ice-water bath to 10 °C, of deionized water (192.3 g) and concentrated HCl (222.2 g).
- a solution of diallylmethylammonium chloride (59.1 g of the 50 percent aqueous solution), acrylamide (14.2 g), and 2,2'-azobis(2-amidinopropane) dihydrochloride (2.7 g of a 20 percent aqueous solution) in deionized water (14.2 g) was heated to 60 °C for 18 hours under a nitrogen atmosphere.
- reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 25.2 g.
- Example 69 Copoly(diallyldimethylarnmonium chloride/acrylamide) (50:50).
- diallyldimethylammonium chloride 49.8 g of a 65 percent solution in water
- acrylamide 14.2 g
- 2,2'-azobis(2-amidinopropane) dihydrochloride 2.7 g of a 20 percent aqueous solution
- deionized water 91.1 g
- the reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 27.8 g.
- Example 70 Functionalization of polydiallylmethylamine with epichlorohydrin.
- the resulting slurry was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 26.8 g.
- Example 71 Copoly(diallyldimethylammonium chloride/poly(ethylene glycol) methyl ether acrylate).
- diallyldimethylammomum chloride (41.5 g of a 65 percent solution in water), poly(ethylene glycol) methyl ether acrylate (3.0 g, Average Mn 454, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane) dihydrochloride (0.3 g) in 2-methyl-2-propanol (60 g) and deionized water (60 g) was heated to 60 °C for 16.5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into isopropanol (2 L) and stirred for at least 15 minutes. The solution was decanted from the precipitated polymer.
- Example 72 CopoIy(diallyldimethylammonium chloride/poly(propylene glycol) methyl ether acrylate).
- diallyldimethylammonium chloride (41.5 g of a 65 percent solution in water), poly(propylene glycol) methyl ether acrylate (3.0 g, Average Mn 202, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane) dihydrochloride (0.3 g) in 2-methyl-2-propanol (60 g) and deionized water (60 g) was heated to 60 °C for 16.5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into isopropanol (2 L) and stirred for at least 15 minutes. The solution was decanted from the precipitated polymer.
- the polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. After decanting, the polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. The washed polymer was dried in a forced-air oven at 70 °C to afford 18.2 g.
- Example 73 Copoly(dialIyldimethylammonium chloride/vinyl alcohol) (50:50).
- diallyldimethylammonium chloride (32.6 g of a 65 percent solution in water), vinyl acetate (10.53 g), and 2,2'-azobis(2-amidinopropane) dihydrochloride (0.64 g) in 2-methyl-2-propanol (60 g) and deionized water (60 g) was heated to 60 °C for 21 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into isopropanol (2 L) and stirred for at least 15 minutes. The solution was decanted from the precipitated polymer. The polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle.
- the polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle.
- the washed polymer was dried in a forced-air oven at 70 °C to afford 11.5 g.
- the reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- Example 74 CopoIy(diallyldimethylammonium chloride/poly(ethy!ene glycol acrylate).
- a solution of diallyldimethylammonium chloride (36.9 g of a 65 percent solution in water), poly(ethylene glycol) methyl ether acrylate (6.0 g, Average Mn 375, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane) dihydrochloride (0.3 g) in deionized water (120 g) was heated to 60 °C for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into acetone (2 L) and stirred for at least 15 minutes. The solution was decanted from the precipitated polymer. The polymer was suspended in acetone (2 L), stirred for at least 15 minutes, and allowed to settle. After decanting, the polymer was suspended in acetone (2 L), stirred for at least 15 minutes, and allowed to settle. The washed polymer was dried in a forced-air oven at 70 °C to afford 20.0 g.
- Example 75 Copoly(diallyldimethylammonium chloride/acrylic acid) (90:10).
- the polymer was suspended in isopropanol (2 L), ground in a blender for at least 5 minutes, stirred for at least 15 minutes, and allowed to settle. The washed polymer was dried in a forced-air oven at 70 °C to afford 35.0 g.
- Example 76 Copoly(diaHyldimethylammonium chloride/acrylic acid) (75:25).
- diallyldimethylammonium chloride 66.97 g of a 65 percent solution in water
- acrylic acid 6.47 g
- 2,2'-azobis(2-amidinopropane) dihydrochloride 0.487 g
- deionized water 175 mL
- the polymer was suspended in isopropanol (2 L), ground in a blender for at least 5 minutes, stirred for at least 15 minutes, and allowed to settle. The washed polymer was dried in a forced-air oven at 70 °C to afford 38.9 g.
- Example 77 Functionalization of poly(diallylmethylamine) with 3- bromopropionic acid.
- a basic solution of polydiallylmethylamine was prepared by mixing polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous solution) overnight. To a portion of the basic solution of polydiallylmethylamine (158.6 g) was added deionized water (141.4 g) and 3-bromopropionic acid (15.5 g). This solution was heated to 50 °C, and then NaOH (16.2 g of a 50 percent aqueous solution) was added. The reaction solution was heated at 50 °C for 18.5 hours.
- reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours.
- the dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 29.2 g.
- Example 78 Functionalization of poly(diallylmethylamine) with 4- bromobutyric acid. To a portion of the basic solution of polydiallylmethylamine (158.6 g;
- Example 77 was added deionized water (141.4 g) and 3-bromobutyric acid (17.0 g). This solution was heated to 50 °C, and then NaOH (16.2 g of a 50 percent aqueous solution) was added. The reaction solution was heated at 50 °C for 18.5 hours. After cooling to room temperature, the reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized water for at least 18 hours. The dialyzed polymer solution was dried in a forced-air oven at 70 °C to afford 20.0 g.
- Example 79 Functionalization of poly(diallylmethylamine) with 2- bromoethanesulfonic acid.
- Example 80 Functionalization of polydiallylmethylamine) with 1,3-propane sultone.
- Example 81 Functionalization of polydiallylmethylamine) with 2- bromoethanol.
- Example 82 Functionalization of poly(diallylamine) with 2-bromoethanol.
- a basic solution of polydiallylamine was prepared by mixing polydiallylamine hydrochloride (519.03 g of a 28.9 percent aqueous solution), deionized water (230.97 g) and NaOH (48.0 g of a 50 percent aqueous solution) overnight.
- Example 83 Copoly[(3-acrylamidopropyl)trimethylammonium chloridej/acrylic acid](90:10).
- Example 84 Copoly[(3-acrylamidopropyl)trimethylammonium chloride]/acrylic acid](75:25).
- Example 85 Copoly(diallyldimethylammonium chloride/poly(ethylene glycol) methyl ether acrylate).
- diallyldimethylammonium chloride 50.0 g of a 50 percent solution in water
- poly( ethylene glycol) methyl ether acrylate 25.0 g, Average Mn 454, obtained from Aldrich Chemical Co.
- 2,2'-azobis(2-amidinopropane) dihydrochloride 0.5 g
- deionized water 190 mL
- Example 86 Copoly[(3-acrylamidopropyl)trimethylammonium chloride /poly(ethylene glycol) methyl ether acrylate].
- the upper liquid layer was decanted from the precipitate, and concentrated on a rotary evaporator to remove most of the tetrahydrofuran.
- the concentrated solution was then poured into diethyl ether, and the light yellow precipitate was filtered and dried under vacuum to afford 2.5 g of solid poly(ethylene glycol) methyl ether acrylate.
- Additional material was isolated from the initial precipitate by mixing it with tetrahydrofuran (250 mL) and heating at 35 °C for 2 hours. The mixture was filtered through celite, and the filtered solution was concentrated on a rotary evaporator to remove most of the tetrahydrofuran. The concentrated solution was poured into diethyl ether, and the light yellow precipitate was filtered and dried under vacuum to afford 3.2 g of solid poly(ethylene glycol) methyl ether acrylate.
- Example 87 Preparation of a copolymer of diallyamine HCL (50% and acylamide (50%) Diallylamine (60 g, 617 mmole) was suspended in water (200 mL) which was acidified with concentrated HCl to pH 1.5 at 10-15 C. Acrylamide (43.85 g, 617 mmol) was added and the reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of 2,2'-azobisisobutyronitrile (500 mg). The reaction mixture was slowly heated to 65 ⁇ C and the heating was continued for 16 hours under nitrogen. The reaction contents were poured into isopropanol (2 L) and the polymer precipitated. The supernatant was removed and replaced with fresh isopropanol (2 L). This process was repeated 2 more times. The polymer was finally collected by filtration and the material was dried under vacuum at 45 C. The polymer was ground, passed through an 80 mesh sieve, and dried again in a vacuum oven to yield 100 g of product.
- Diallylamine
- Example 88 Preparation of a copolymer of (3-acrylamidopropyl) trimethylammonium choloride (75 mole %) and acrylamide (25 mole%)
- a 30-L reaction vessel was charged with (3-acrylamidopropyl) trimethylammonium chloride (2481 g of 50 percent solution, 6 moles) and acrylamide (142.16 g, 2 moles).
- Isopropanol (6 L) was added and the vessel was purged with nitrogen for 10 minutes prior to the addition of 2,2'- azobisisobutyronitrile (5.28g).
- the reaction mixture was heated to 70 C for 21 hours under nitrogen.
- the reaction mixture was collected in a bucket, the supernatant was decanted, and the material was suspended in boiling isopropanol (3 L). The mixture was sti ⁇ ed with overhead stirrer for 20 minutes.
- Example 89 Preparation of a copolymer of (3-acrylamidopropyl) trimethylammonium chloride (75 mole%), crylamide (20 mole%) and N- octoylacrylamide (5 mole%)
- a three-necked round-bottomed flask (1 L) was charged with (3- acrylamidopropyl) trimethylammonium chloride (62 g of 50 percent solution, 150 mmol), acrylamide (2.84 g, 40 mmol), octylacrylamide (1.83 g, 10 mmol) and isopropanol 160 mL.
- the mixture was purged with nitrogen for 10 minutes prior to the addition of 2,2 '-azobisisobutyronitrile (132 mg).
- the reaction mixture was heated to 70 ⁇ C for 16 hours. At the end of reaction, the solvent was removed from the reaction mixture and the precipitated polymer was poured into boiling isopropanol (1 L).
- Example 90 Preparation of the methylenebisacrylamide (1 mole%) cross- linked copolymer of (3-acrylamidopropyl) trimethylammonium choloride (75%)), acrylamide (20 mole%) and N-dodecylacrylamide (5 mole%)
- the solvent was removed from the reaction mixture.
- the precipitated polymer gel was suspended in boiling isopropanol (1 L).
- the solvent was replaced with fresh boiling isopropanol.
- the process was repeated 3 more times.
- the polymer was suspended in isopropanol (1 L) and ground in a blender.
- the polymer was collected and dried under vacuum at 60 °C.
- the gel was washed with water (4 x 2.5 L) followed by isopropanol (3 4 L).
- the polymer was dried in a vacuum oven to yield 60 g of product.
- Example 91 Preparation of poly[(n-viny!imidazole-co-(l-vinyl-3- methylimidazole-co-(l-vinyl-3-dodecylimidazole)] 20/75/5
- n-vinylimidazole 500 g; 5.31 moles
- deionized water 250 mL
- HCl HCl
- Enough water was added to make the reaction solution 25 percent solids and this was degassed via nitrogen purge for 1 hour.
- the reaction was heated to 60 °C at which point was added 2,2'-azobis (2-amidinopropane) dihydrochloride (2.5 g) dissolved in ⁇ 2 mL of water.
- the reaction mixture was heated to 45 °C for 3 hours to kill any unreacted dimethyl sulfate.
- the pH was adjusted to 1.2 with HCl and the mixture was triterated into isopropanol.
- the liquid was poured off, the polymer was re-dissolved in deionized water and re-triterated into isopropanol.
- the polymer was dissolved in 300 mL of deionized water and 125 mL of Amberlite CI- ion exchange resin beads for 4 hours. The polymer was filtered off, the beads were rinsed with water and the polymer solution was allowed to dry in a convection oven at 60 °C to yield 51.2 g of solid.
- Example 92 Preparation of poly[(diallyl dimethyl ammonium chIoride)-co-(n- vinyl glycine)] 70/30
- diallyldimethyl ammonium chloride 66.85 g of 65 percent solution in water, 43.45 g solids, 0.2687 moles
- allylamine HCl 24.12 g of 27.16 percent solution based on allylamine charged in water, 0.1149 moles
- deionized water 75.69 mL
- reaction mixture was degassed via nitrogen purge for 1 hour and then heated to 60 °C at which time 2,2'-azobis (2-amidinopropane) dihydrochloride (0.25 g) in ⁇ 1 mL of water was added. This was followed 30 minutes later with an additional charge of 2,2'-azobis (2-amidinopropane) dihydrochloride (0.25 g in ⁇ 1 mL of water). Further additional charges were made at 5 hours, 20 hours, and 28 hours. At 48 hours the temperature was raised to 80 °C for 1 hour and then turned off and the reaction was allowed to cool to room temperature.
- diallyldimethylammonium chloride (891 g of 65 percent solution in water,; 579.15 g solids; 3.58 moles), allylamine HCl (321.5 g of 27.16 percent solution based on allylamine charged in water, 1.53 moles), and deionized water (454 mL) to make 40 percent solids (based on un-protonated monomers charged).
- the reaction mixture was degassed via nitrogen purge for 1 hour and then heated to 60 °C at which time 1.67 g of 2,2'-azobis (2-amidinopropane) dihydrochloride in ⁇ 2 mL of water was added.
- the reaction was allowed to cool to room temperature before adding chloroacetic acid (30 g ; 0.3177 moles) and the pH was readjusted to 10. The reaction was allowed to stir at 40 °C for 20 hours. The polymer was then precipitated into acetone and the liquid was decanted. The polymer was redissolved in deionized water and re-triterated into acetone; this procedure was repeated once more. The polymer was then dissolved in deionized water and the pH was adjusted to ⁇ 2 with HCl (37 percent) and the triteration into acetone procedure was repeated three more times. The polymer was dissolved in water and placed in a convection oven at 60 °C to dry to 36.9 g of glassy solid.
- Example 95 Preparation of Poly[((3-acrylamidopropyl) trimethylammonium chloride)-co-(acry!amide)-co-(n-octadecylacrylamide)] 60/35/5
- 2,2 '-Azobisisobutyronitrile (0.1 g) was added when the temperature reached 62 °C and all of the reactants were dissolved. The reaction was allowed to heat with stirring and nitrogen purge for 4 hours. Isopropanol (200 mL) was added to the flask and the heat was turned off. The precipitated polymer was stirred in the hot isopropanol for ten minutes before pouring off the liquid. The polymer was scraped out of the flask and dried in a 60 °C convection oven to yield 21.2 g of solid.
- diallylamine (8.88 g; 0.092 moles)
- deionized water (20 mL).
- the mixture was cooled in an ice bath and 50 percent concentrated HCL in water was slowly added dropwise until the pH reached 0.86.
- Acrylamide (19.49 g; 0.2749 moles), 2,2'-azobis (2-amidinopropane) dihydrochloride (0.31 g), and deionized water (20 mL) were added.
- the reaction mixture was degassed with nitrogen for 30 minutes and the temperature was raised to 55 °C at which point the flask was placed in an ice bath to control the exotherm (maximum temperature 78 °C).
- Example 97 Preparation of PoIy[(diaIlyl ammonium chloride)-co- (acrylamide)] 75/25
- diallylamine (20.69 g; 0.213 moles)
- deionized water (20 mL).
- the mixture was cooled in an ice bath and 50 percent concentrated HCL in water was added dropwise until the pH reached 0.9.
- Acrylamide (5.05 g; 0.0711 moles), 2,2'-azobis (2-amidinopropane) dihydrochloride (0.335 g), and deionized water (20 mL) were added.
- the reaction mixture was degassed with nitrogen for 30 minutes and the temperature was raised to 65 °C.
- Example 98 Preparation of Poly [((3-acrylamidopropyl) trimethylammonium chloride)-co-(acrylamide)-co-(n-octadecylacrylamide)] 50/45/5
- Isopropanol 200 mL was added to the flask and the heat was turned off. The precipitated polymer was sti ⁇ ed in the hot isopropanol for ten minutes before pouring off the liquid. The polymer was scraped out of the flask and dried in a 60 °C convection oven to yield 18.3 g of solid.
- the model consists of male, Sprague Dawly rats, 160 g, housed individually in wire mesh cages. They were acclimated to the facility for six days, during which time they were fed a chow based diet supplemented with 15 percent lard by weight. Feed and water were provided ad libitum. The animals were then randomly assigned to groups of four and fed test diets for three days. The test diet was also a chow based feed. A lipase inhibitor (Orlistat) was added at 0.04 percent by weight and the polymer was added at 0.30 percent by weight.
- Orlistat A lipase inhibitor
Abstract
Description
Claims
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PCT/US1999/015958 WO2001005408A1 (en) | 1999-07-14 | 1999-07-14 | Fat-binding polymers, optionally combined with lipase inhibitors |
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AU (1) | AU774636B2 (en) |
CA (1) | CA2379308A1 (en) |
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CN109071820A (en) * | 2016-05-10 | 2018-12-21 | 美国陶氏有机硅公司 | Organic silicon block copolymer and its preparation and application with amino-functional end-capping group |
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US7049345B2 (en) | 2001-06-29 | 2006-05-23 | Genzyme Corporation | Fat-binding polymers |
WO2011062607A1 (en) * | 2009-11-17 | 2011-05-26 | Dow Global Technologies Inc. | Amine adducts |
US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
IT1404163B1 (en) | 2011-02-01 | 2013-11-15 | Chemi Spa | PROCESS FOR THE PREPARATION OF RETICULATED POLYALLYLAMINS OR THEIR PHARMACEUTICAL ACCEPTABLE SALTS |
RU2690672C2 (en) | 2014-08-11 | 2019-06-05 | Перора Гмбх | Method of inducing satiety |
MX2017001628A (en) | 2014-08-11 | 2017-07-28 | Perora Gmbh | Formulation comprising particles. |
EP3319589A1 (en) | 2015-07-07 | 2018-05-16 | perora GmbH | Composition comprising satiety-inducing particles |
US11234935B2 (en) | 2015-07-07 | 2022-02-01 | Perora Gmbh | Method of inducing satiety |
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- 1999-07-14 MX MXPA02000492A patent/MXPA02000492A/en not_active Application Discontinuation
- 1999-07-14 WO PCT/US1999/015958 patent/WO2001005408A1/en active IP Right Grant
- 1999-07-14 EP EP99934037A patent/EP1196181A1/en not_active Withdrawn
- 1999-07-14 CA CA002379308A patent/CA2379308A1/en not_active Abandoned
- 1999-07-14 AU AU49957/99A patent/AU774636B2/en not_active Ceased
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CN109071820A (en) * | 2016-05-10 | 2018-12-21 | 美国陶氏有机硅公司 | Organic silicon block copolymer and its preparation and application with amino-functional end-capping group |
CN109071820B (en) * | 2016-05-10 | 2021-08-17 | 美国陶氏有机硅公司 | Silicone block copolymers with amino-functional end-capping groups and methods of making and using the same |
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AU4995799A (en) | 2001-02-05 |
AU774636B2 (en) | 2004-07-01 |
WO2001005408A1 (en) | 2001-01-25 |
HK1046092A1 (en) | 2002-12-27 |
IL147361A0 (en) | 2002-08-14 |
CA2379308A1 (en) | 2001-01-25 |
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MXPA02000492A (en) | 2002-07-02 |
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