WO1995019384A1 - Crosslinked polymeric ammonium salts - Google Patents
Crosslinked polymeric ammonium salts Download PDFInfo
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- WO1995019384A1 WO1995019384A1 PCT/US1995/000713 US9500713W WO9519384A1 WO 1995019384 A1 WO1995019384 A1 WO 1995019384A1 US 9500713 W US9500713 W US 9500713W WO 9519384 A1 WO9519384 A1 WO 9519384A1
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- nitrogen atoms
- ammonium salt
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- crosslinked polymeric
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—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
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0206—Polyalkylene(poly)amines
- C08G73/0213—Preparatory process
- C08G73/0226—Quaternisation of polyalkylene(poly)amines
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
Definitions
- This invention concerns novel, crosslinked
- polymeric ammonium salts and processes for their preparation. Uses for these compositions are as absorbents, adsorbents, electroconductive agents, charge transfer agents, chelating agents and ion exchange resins. These salts are also useful as bile acid sequestrants, i.e., when administered orally, the polymers lower blood cholesterol levels in mammals.
- crosslinked polymers containing quaternary ammonium groups in the polymer backbone which are separated by trimethylene groups No mention is made of the use of polymers containing ammonium salts which are not quaternary ammonium salts.
- U.S. Patent 4,775,384 describes the reaction of various organic compounds containing two halogen groups with various diamines to form polymeric ammonium salts . These salts are described as water soluble, and are thus not crosslinked. After further reactions, they are described as being useful as fiber finishes .
- U.S. Patent 4,147,586 describes the reaction of certain dihaloalkanes with alkylene diamines to form "adducts" which are water soluble.
- the adducts are useful, after reaction with an epihalohydrin, for increasing the wet strength of paper.
- Several different types of bile acid sequestrants are known. Some of these are polymers which contain ammonium salts (amine groups in the salt form) which are bound to or are part of a polymer molecule. Such polymers vary in their ability to bind bile acids, their toxicity and their ease of administration. Thus, improved bile acid sequestrants are still being sought.
- crosslinked polymers containing amine groups as bile acid sequestrants are crosslinked polymers containing amine groups as bile acid sequestrants.
- crosslinked styrenes containing quaternary ammonium groups is described.
- Such resins which are also useful as ion exchange resins, are believed to be the active ingredient in the commercially available cholestyramine which is used to lower blood cholesterol levels.
- ammonium salts that are not quaternary ammonium salts.
- U.S. Patent 5,236,701 describes a crosslinked polymeric material useful as a bile acid sequestrant which has amine group on polymer branches which are end groups. The amine groups are not part of the
- This invention includes crosslinked polymeric ammonium salts, useful as bile acid sequestrants, as absorbents or as charge transfer agents, said salts comprising ammonium nitrogen atoms linked by segments to other ammonium nitrogen atoms wherein:
- each R 1 and each R 2 is independently alkyl, said alkyl
- each Z is independently a
- hydrocarbylene radical containing 2 to 50 carbon atoms, said hydrocarbylene radical optionally containing one or more groups, independently selected from the group consisting of hydroxyl, ether, amino, thioether, keto, or silyl groups and heterocyclic rings;
- ammonium nitrogen atoms are secondary ammonium nitrogen atoms
- crosslinked polymeric ammonium salt is insoluble in water; provided that at least some of said ammonium nitrogen atoms are part of a
- This invention includes a method for sequestering bile acids, comprising, contacting in an aqueous medium a bile acid and a crosslinked polymeric ammonium salt, wherein in said salt:
- Y is an n-alkylene group or alkyl substituted n-alkylene group, wherein said n-alkylene group has 7 to about 15 carbon atoms;
- hydrocarbylene radical optionally containing one or more groups selected from the group consisting of hydroxyl, ether, ester, amino, thioether, keto, silyl group and heterocyclic rings;
- ammonium nitrogen atoms are secondary ammonium nitrogen atoms.
- substituents e.g. hydroxy, ether, amino, thioether, keto or silyl group, on the hydrocarbylene contain 1 to 50 carbon atoms, more preferably 1 to 30 carbon atoms.
- crosslinked polymeric ammonium salt has a B max /K d value for cholate of greater than 0.75.
- This invention also includes preferred methods for the preparation of the crosslinked polymeric ammomium salts of this invention and pharmaceutically acceptable salts thereof This invention also also includes improved methods for the preparation of the crosslinked polymeric
- ammonium salts of this invention having improved bile acid sequestrant properties, wherein said improved
- methods comprise carrying out the polymerization step for the preparation of the the crosslinked polymeric ammonium salt of the invention in the presence of a
- the present invention also includes methods for the treatment of hypercholesterolemia and/or lowering blood plasma cholesterol levels in a mammal comprising
- the present invention also includes pharmaceutical compositions comprising a therapeutically effective amount of a crosslinked polymeric ammonium salt as described above and a pharmaceutically acceptable carrier.
- kits comprising one or more containers containing pharmaceutical dosage units comprising a crosslinked polymeric ammonium salt as described above, for use for the treatment of hypercholesterolemia, for sequestering bile acids, and/or for the lowering of blood cholesterol levels.
- the crosslinked polymeric ammonium salt compounds of the present invention can also be administered in combination with one or more additional therapeutic agents. Administration of the crosslinked polymeric ammonium salts of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
- the present invention also includes methods of treating hypercholesterolemia in a mammal by administering a crosslinked polymeric ammonium salt as described above in combination with one or more additional therapeutic agents which may be selected from but not limited to: an inhibitor of acyl-coenzyme A: cholesterol
- ACAT O-acyltransferase
- HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase
- MEVACOR ® lovastatin
- LPID ® gemfibrozil
- ATROMID-S ® clofibrate
- probucol LORELCO ®
- crosslinked is meant a polymer which has a network structure.
- a common test to determine if a polymer is crosslinked is to try to dissolve the polymer in a liquid that is normally a solvent for that polymer. Linear or branched, but not crosslinked, polymers will dissolve in the solvent.
- Crosslinked polymers do not dissolve, although they may swell to some degree.
- the polymeric ammonium salts described herein, when not crosslinked, are generally soluble in water or other polar solvents.
- the polymeric ammonium salts swell in water, often to form gel-like materials.
- polymeric ammonium salts of this invention may be used in dry or nearly dry form or swollen in water. It is preferred if the polymeric ammonium salt used has a swell factor of at least about 4, preferably about 5 to 30 and more preferably about 10 to 30. The swell factor is taken as the ratio of the weight of water imbibed by the polymer divided by the weight of the polymer used. It is believed that the crosslinked polymeric ammonium salts that swell to the preferred levels have certain advantages as blood plasma cholesterol level lowering agents, such as increased capacity to sequester bile acids and soft gel texture which leads to less
- an ammonium salt or ion is meant a nitrogen atom bonded to four other atoms, for example in the ammonium ion itself, to four hydrogen atoms.
- a primary ammonium ion the nitrogen atom is bonded to three hydrogen atoms and one carbon atom
- a secondary ammonium ion it is bonded to two carbon atoms and two hydrogen atoms
- a tertiary ammonium ion to three carbon atoms and one hydrogen atom in a quaternary ammonium ion to 4 carbon atoms.
- at least 25% of the ammonium nitrogen atoms are secondary ammonium nitrogen atoms, preferably at least about 40%.
- primary ammonium nitrogen atoms are 15 to 30%, secondary ammonium nitrogen atoms are 40-60%, tertiary ammonium nitrogen atoms are 15 to 30% and quaternary ammonium nitrogen atoms are less than 5%, of all of the total ammonium nitrogen atoms in the polymer.
- the relative abundance for each type of ammonium is 15 to 30%, secondary ammonium nitrogen atoms are 40-60%, tertiary ammonium nitrogen atoms are 15 to 30% and quaternary ammonium nitrogen atoms are less than 5%, of all of the total ammonium nitrogen atoms in the polymer.
- nitrogen atom may be determined using the method described in Example 53.
- Each nitrogen atom of an ammonium salt has one positive charge, and a counterion for the positive charge of each ammonium ion is close by.
- the counterion may be any negative ion whose conjugate (Bronsted) acid is capable of protonating the conjugate base of the ammonium salt.
- the counterion should be biologically compatible, that does not cause substantial undesired physiological changes. Suitable biologically compatible counterions include chloride, bromide, iodide, sulfate, phosphate, acetate, ascorbate, carbonate, bicarbonate, nicotinate, salicylate, tartrate and citrate. Chloride ion is an especially preferred counterion.
- the nitrogen atoms of the ammonium salts (ions) of the polymer are located between polymer segments, unless they are end groups. At least about 25% of these groups, designated herein as Y, linking these nitrogen atoms are independently selected from n-alkylene groups having 7 to about 20 carbon atoms.
- n-alkylene herein is meant the group -(CH2) b - wherein b is a specified integer, in this instance 7 to about 20.
- Y can be represented by the formula -(CR 1 R 2 )b-, where b is an integer from 7 to 20, and each R 1 and R 2 is independently alkyl, preferably having 1 to 20 carbon atoms and more preferably having 1 to 10 carbon atoms, or hydrogen.
- This n-alkylene group Y may also be substituted with alkyl groups, and is then in effect a branched alkylene group. It is preferred if the n-alkylene group has 7 to 14 carbon atoms, and more preferred if it has 9 to 12 carbon atoms. It is contemplated that other hydrocarbylene groups, such as ones wherein the distance between nitrogen atoms is equivalent to at least 7 methylene groups, are also operative .
- hydrocarbylene groups containing 2 or more carbon atoms, preferably 2 to 50 carbon atoms, that is there must be at least two carbon atoms between the nitrogen atoms.
- hydrocarbylene herein is meant a divalent radical containing only carbon and hydrogen.
- the hydrocarbylene group Z may be substituted with various substituents or contain in-chain groups containing heteroatoms. It is preferred if the hydrocarbylene group is saturated. Substituents or in-chain groups may include hydroxy, alkoxy, ether, ester, amino, thioether, keto, silyl groups or
- substituents are ether and amino groups. It is preferred if the hydrocarbylene group Z is an n-alkylene group containing 2 to 14 carbon atoms. It is also preferred if the subst ituent contains 1 to 50 carbon atoms , more preferably 1-30 carbon atoms, most preferably 1 to 20 carbon atoms. Many of the nitrogen atoms located between polymer segments Y and Z (alternatively connected by segments Y and Z), assuming Z is present, are part of the
- the polymer network may be thought of as a 3 dimensional latticework, with some segments of the lattice not being connected at one end to the lattice. These unconnected segments are usually thought of as polymer ends.
- Part of the crosslinked network is that the particular segment or group (which may contain one or more nitrogen atoms) in question is joined at both ends of the segment or group to a crosslinking site (or crosslinking branch point) of the 3 dimensional lattice.
- a segment which is connected (eventually) at both ends to the lattice (and any nitrogen atoms it contains) is "part of the crosslinked network. It is believed that in these crosslinked polymeric ammonium salts, nitrogen atoms are often the actual crosslinking branch sites, and of course, these nitrogen atoms are part of the crosslinked network.
- alkyl is intended to include both branched and straight-chain saturated aliphatic
- hydrocarbon groups having the specified number of carbon atoms (the number of carbon atoms may be specified, for example, as “C 1 -C 10 " to denote alkyl having 1 to 10 carbon atoms).
- alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like;
- alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
- alkylene alkenylene
- phenylene cycloalkylene
- alkyl alkenyl
- phenyl cycloalkylene
- groups may alternatively and equivalently be denoted as -(alkyl)-, -(alkyenyl)-, -(phenyl)-, -(cycloalkyl)-, and the like, respectively.
- hydrocarbylene includes any hydrocarbon group such as, by way of example and without limitation, alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, alkylcycloalkylalkyl, alkylcarbocycle, or carbocyclealkyl groups, which are connected by two bonds to the rest of the structure of crosslinked polymer of the present invention.
- substituted hydroxy, ether, amino, thioether, keto, silyl groups, or heterocyclic rings it is meant that the hydrocarbylene group is substituted with one or more (preferably 1-5, independently selected) -OH,
- -S(C 1 -C 10 alkyl), -(C 1 -C 10 alkyl) S (C 1 -C 10 alkyl), O, (C 1 -C 10 alkyl), -SiH(C 1 -C 10 alkyl) 2, or -(heterocycle) groups.
- hydrocarbyl includes any hydrocarbon group such as, by way of example and without limitation, alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, alkylcycloalkylalkyl, alkylcarbocycle, or carbocyclealkyl groups, which are connected by one bond to the rest of the structure of crosslinked polymer of the present invention.
- Such hydrocarbyl group may contain an in-chain or substituent group as described above for a hydrocarbolene group.
- Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge
- alkylthio represents an alkyl group of indicated number of carbon atoms attached through an sulfur bridge
- cycloalkyl is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl
- biycloalkyl is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane
- carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
- carbocyles include, but are not limited to, cyclopropyl,
- cyclopentyl cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
- heteroaryl or “heterocyclic ring” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
- pyridinyl pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, ß-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidin
- substituted means that any one or more hydrogen on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- 2 hydrogens on the atom are replaced.
- bifunctional organic compound refers to a compound which may be represented by the formula X-Y-X and/or X-Z-X, where Y and Z are defined above, and X is a suitable leaving group useful for amine alkylation reactions.
- X may be independently selected from, but not limited to, the following: halides, epoxides, derivatized alcohols, sulfonate esters, aziridines, episulfides, sulfate esters, diazo groups.
- alkylating agent Y or Z, as defined above, is the group to which the suitable leaving group
- the diamine compound may be represented by
- H 2 N-Y-NH 2 and/or H 2 N-Z-NH 2 where Y or Z, as defined above, is the group to which the two amino groups are bound.
- the bifunctional organic compound for example, dihalide
- the diamine must contain Y as described above.
- the Y or Z group should be of such a size that the suitable leaving groups (for example, halogen atoms) are the equivalent of about 7 or more methylene groups apart, that is be separated by 7 methylene groups or an equivalent distance if not separated by methylene groups . It is believed that if this minimum separation of the bifunctional organic compound (for example, dihalide) and/or some of the diamine must contain Y as described above.
- the Y or Z group should be of such a size that the suitable leaving groups (for example, halogen atoms) are the equivalent of about 7 or more methylene groups apart, that is be separated by 7 methylene groups or an equivalent distance if not separated by methylene groups . It is believed that if this minimum
- bifunctional organic compound leaving groups is not present, the bifunctional organic compound tends to "back bite" after the first leaving group has reacted with an amine, to give an undesirable cyclic structure.
- the bifunctional organic compound be X-Y-X.
- Groups Y and Z may be selected independently at each position in a particular polymer.
- dihalides include, but are not limited to, 1,10-dibromodecane, 1,12-dibromododecane,
- 1,9-dibromononane 1,7-dibromoheptane, 1,8-diiodooctane, 1,8-dibromo-3-ethyloctane, and 1,9-dibromodecane.
- Useful diamines include, but are not limited to, ethylene diamine, 1,6-diaminohexane,
- 1,12-diaminododecane 2-methyl-1,5-diaminopentane, 1,4-bis(aminomethyl)cyclohexane, 1,3-diaminopentane, diethylenetriamine, 1,4-bis(3-aminopropyl)piperazine, 1,4-cyclohexanediamine, 5-amino-1-aminomethyl-1,3,3-trimethylcyclohexane, 1,3-propanediamine,
- the polymeric ammonium salts can also be made by reaction of a diamine with a diepoxide.
- a diamine is the diamine in which the nitrogen atoms are connected by an n-alkylene group (which may be alkyl substituted) containing 7 to about 20 carbon atoms. See Examples 57-63 for the preparation of such sequestrants.
- the ammonium salts are formed by neutralization of the amines with acids.
- polyamines and their salts, as described herein, may have nitrogen atoms that are further substituted, typically by reaction with (substituted) alkyl halides to form for example, secondary amine
- the group Q which is further substituted on a nitrogen is a hydrocarbyl group containing 1 to 50 carbon atoms, and may contain one or more, preferably 1 to 5, in-chain or substituent
- the present invention also includes improved processes for the preparation of the crosslinked
- polymeric ammonium salts comprising Y and optionally Z groups, as defined above.
- the process for the preparation of the crosslinked polymeric ammonium salts of the invention comprises a
- polymerization step (including gelation) and also preferably comprises one or more of the following steps (which are further described in detail below): a purification step; an ion exchange step; a size
- reduction step may be carried out after either the polymerization, purification, drying, or ion exchange steps. Additional steps may be added, some steps may be combined and/or done in the same equipment, and/or the order of some steps may be changed in order to improve the overall process.
- the purification and ion exchange steps may be carried out concurrently in a single combined step; polymerization and size reduction may be combined;
- drying and size reduction may be combined; there may be multiple size reduction steps; polymerization, size reduction, purification, and ion exchange may be done in the same equipment; purification, ion exchange, and size reduction may be combined and/or done in the same equipment; and other such combinations and/or exchanges may be done which would improve the overall process.
- the process and conditions for the preparation of the crosslinked polymeric ammonium salts include, but are not limited to, those processes and conditions described in detail below.
- the polymerization step (including gelation) is conducted in such a manner as to allow control of the reactant mole ratio, temperature, time, solvent composition, reagent feed rate, order and mode of reagent addition, monomer concentration, mixing and other reaction variables.
- the polymeric ammonium salts can be made from the above described diamines and bifunctional organic compounds (for example, dihalides or diepoxides) by dissolving the reactant monomers, either separately or together, in a suitable solvent, typically a polar solvent, such as described below.
- the reactants are then mixed under controlled conditions using a suitable reactor. Following heating and agitation, the reaction mixture forms a gel or granular crumb-like solid, i.e. undergoes gelation as discussed below.
- the crude polymeric ammonium salts are ready for purification, ion exchange, size reduction, and/or drying if so desired.
- gelation is meant the point at which the polymer becomes insoluble due to crosslinking.
- a swollen gel will form at the point at which the polymer becomes insoluble, a
- the gel may become a crumb-like solid upon breaking either by agitation in the reactor or high shear milling, as described below.
- the suitable solvent used in the polymerization reaction step may be a single compound or a mixture of compounds. All of the starting materials that react to form the crosslinked polymer should be soluble in the solvent.
- Useful solvents include polar compounds, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, hexamethyl phosphoramide (HMPA) , n-methyl pyrrolidone (NMP), isopropanol, methanol, ethanol and other lower alcohols and lower ethers. These may be used in combination with each other or alone.
- Especially preferred solvents are mixtures of N,N-dimetriylformamide and methanol or N,N-dimethylacetamide and methanol.
- the reactant monomer concentrations of the reactant solutions when taken individually, range from 5% to 60% by weight (wt) relative to the total reaction solution weight.
- the overall monomer concentration in the reactor is 5% to 60% by wt where the preferred operating range is 35% to 45% by wt.
- the overall solids loading, or monomer concentration, in the reactor is 5% to 60% by wt where the preferred operating range is 35% to 45% by wt.
- the monomer concentration in the reaction may effect the crosslink density of the product polymer.
- the mole ratio of reactants as well is controlled during the polymerization. Approximately equimolar amounts of the diamine and alkylating agent are reacted.
- a suitable range for the mole ratio of the bifunctional organic compound to the diamine compound is about 0.9 - 1.4, wherein the preferred range is about 1.0 - 1.20.
- the preferred range may be selected to produce a polymer product having the desired crosslink density, as discussed below.
- the polymerization may be carried out under a wide range of temperatures, ranging from about -5° C to the boiling points of the solvents (or lower boiling ingredient).
- the practical operating temperatures are -5° C - 45° C during the initial reactant mixing and 60° C - 120° C following the initial reactant mixing.
- the preferred ranges are 0° C - 40° C and 75° C - 85° C, respectively.
- the cooler initial reactant mixing temperature allows for control of exothermic reaction.
- the polymerization step may be carried out in the presence or absence of a suitable base to neutralize the acid by-product of the polymerization reaction if an acid by-product is produced by the polymerization reaction.
- suitable bases include, but are not limited to, sodium carbonate or potassium carbonate. Such suitable base is preferably present in an amount of 1-50 mole % relative to the bifunctional organic compound, and preferably in the amount of 10-25 mole %.
- the reaction time for the polymerization step may be varied widely according to the diamine and
- bifunctional organic compound also referred to herein as an alkylating agent
- the reaction will take a few minutes to several days before the gelled crosslinked polymeric ammonium salt of the invention is formed. The most typical range is 0.5 - 24 hours (0.5 to 8 hours being preferred) before gelation occurs with an additional 1 - 16 hour hold period to ensure completion of reaction.
- the polymerization reaction is preferably mixed or agitated during the reaction.
- the intensity of reaction mixing can be changed during different stages of the reaction.
- the reaction mixture is well stirred prior to the gel point or gelation.
- Mixing during and after gelation is not critical on the small scale, however, on the large multikilogram reaction scale, mixing during and after the gelation becomes important.
- Mixing during the polymerization reaction also facilitates product removal by preventing the polymer from forming a single solid mass in the reactor and the gel particle size can be controlled by the judicious selection of the mixing speeds. In general, the faster the mixing during and after gelation, the smaller is the resulting gel particle size of the polymeric ammonium salt present in the reactor.
- the rate and order of reactant addition to the reactor may be controlled.
- the reactants may be added either concurrently or sequentially in any order separately into the reactor, preferably with the bifunctional compound being added subsequent to the diamine.
- the rate of addition of the second reactant to the first reactant in the reactor be sufficiently fast so as to minimize addition of the second monomer after gelation of the reaction mixture.
- the reactant rate of addition is not critical.
- the reactants may be added at the same rate (based on equivalents, volumes, and/or weights) where completion of addition for both reactants is simultaneous ("cofeeding"), or the reactants may be added at different rates such that the completion of addition for either reactant continues beyond completion of addition of the other, but preferably prior to gelation.
- Suitable reactor equipment for the polymerization reaction will depend on the scale of reaction.
- Polymerization is preferably carried out in a reactor suitable for mixing the liquid solvents and solid materials while maintaining temperature control of the reactor's ingredients.
- a reactor suitable for mixing the liquid solvents and solid materials while maintaining temperature control of the reactor's ingredients.
- continuous flow reactors such as, by way of example and without limitation, extruders, heat exchangers, in-line mixer and/or a combination of mixer reactors and continuous flow through reactors may also be used.
- crosslink density (as measured by the swell factor in water) of the crosslinked polymeric ammmonium salt of the invention can be controlled by judicious use of solvents, temperature and reaction time during the polymerization step. Other factors affecting crosslink density are monomer mole ratios and concentrations used in the reaction. Some suitable solvents (e.g. H 2 O, acetonitrile, ethers, methanol, EtOH), when used alone, produce polymers that swell very little in water.
- solvents e.g. H 2 O, acetonitrile, ethers, methanol, EtOH
- Mixtures of some suitable solvents can produce highly swellable polymers. Short reaction times and/or lower temperatures produce less crosslinking and a higher degree of swelling.
- Crosslinking can also be accomplished by using small amounts of tri- or higher functionality amines, epoxides or halides (see Example 67). Crosslinking can also be accomplished by exposing the uncrosslinked polymeric ammonium salt to ionizing radiation.
- the polymeric ammonium salt when used for bile acid sequestration, preferably should have a swell factor of at least about 4 in water.
- the degree of swellability of the polymer is determined by several major factors. One of these is the degree of salt formation in the polymer, that is what percentage of the amino nitrogen atoms present are in their salt form. The higher this percentage, the more the polymer will swell. It is preferred if at least 80% of the amino groups are in their salt form, and more preferred if at least about 90% are in the salt form. Included within the definition of "polymeric ammonium salt" herein is a polymer where at least about 50% of the amino groups in the polymer are in their salt form.
- Another factor controlling swellability is the hydrophilicity of the groups between nitrogen atoms. Generally, the more carbon atoms these groups contain, the less hydrophilic they are, and the less the polymer will swell in water. The swell may be affected by the selection of counterion.
- the final controlling factor is crosslink density. Typically, the higher the crosslink density, the less the polymer will swell.
- reaction temperature contributes to
- a swell of essentially zero is obtained in media which do not dissolve the reactants.
- Swell is very low in interfacial systems in which dibromodecane is dissolved in an organic phase and hexamethylenediamine in water.
- the swell can also be controlled by neutralizing the acid by-product, which is generated, by the addition of bases such as sodium carbonate, potassium carbonate or an organic amine. Other nonnucleophilic bases may also be used.
- bases such as sodium carbonate, potassium carbonate or an organic amine.
- Other nonnucleophilic bases may also be used.
- the formation of higher swell polymers is promoted by solvents which dissolve both reactants, especially dipolar, aprotic solvents. Purification and Counterion Exchange of Product Polymer
- polymeric ammonium salt counterion is included in the polymerization step, such template is removed from the desired product polymeric ammonium salt polymer by such purification step. If it is desired to remove this uncrosslinked (and therefore soluble) fraction, this can be done by extracting the crosslinked (insoluble) polymeric ammonium salt with a suitable solvent for extraction in which the
- the purification step (removal of impurities) and the ion exchange step (to change the polymeric ammonium salt counterion) can be carried out and accomplished simultaneously by way of adding a suitable solvent to form a gel, adding a base, such as ammonium hydroxide or NaOH, to form a salt with the original counterion, removing the salt by washing the polymer, and then reacidifying with the conjugate acid of the counterion desired. Procedures of this type are well known in the art.
- Suitable bases for the extraction purification and ion exchange steps include inorganic bases, such as ammonia, metal hydroxides, metal alkoxides, metal carbonates, and organic bases, such as organic amines.
- extraction purification and ion exchange steps include inorganic acids, such as HCl, and organic acids, such as alkyl and aromatic acids.
- the solvents used for the purification and/or ion exchange steps are those in which the materials needed for ion exchange are at least somewhat soluble and preferably those that swell the polymer such as, by way of example and without limitation, the following solvents (or mixtures thereof) : water, alcohols, polar protic solvents, polar aprotic solvents, solvents containing the conjugate acid of the desired counterion, solvents containing the desired base for removal of the undesired original couterion, and solvents containing salts of the desired counterions. It is preferred to use water and one or more of the above listed bases or acids for the ion exchange step in the process. It is preferred that the solvents be sufficiently volatile to allow relatively easy removal during drying.
- purification and counterion exchange should preferably be in the range of about pH 2-8 and more preferably pH 3-7.
- Methods used for the separation of solids and liquids in the extraction purification of the polymeric ammonium salt product include, but are not limited to, Soxhlet extraction, filtration, centrifugation, and/or other such methods used for the separation of solids and liquids.
- Counter-current extraction methods may be used in the purification step.
- a wide variety of equipment may be employed. These include but are not limited to metal or polymer based screens, cloths, fritted or scintered glass or metal, depth filtration medium, and/or membranes.
- the optimal means for separation will vary according to the specific polymeric ammonium salt, the solvent and/or solvent mixture being employed, and the state of ionization of the polymer.
- Size reduction also referred to herein as milling of the polymeric ammonium salt gel particles obtained after or during either polymerization, purification, ion exchange and/or drying may be accomplished by several means.
- gel particle size reduction of the product polymer is typically and preferably
- the particle size reduction may be done in either the wet, damp, frozen or dry state of the crosslinked polymeric ammonium salt product.
- Mill types useful for particle size reduction include, but are not limited to, a pin mill, hammer mill, cutting mill, rotor-stator mill, media mill, attritor, jet mill, air classifying mill, opposing air jet mill, and/or sonicator.
- the milling may be done on either a batch, semibatch, or continuous flow through basis, the preference of either being dictated by the location of the mill step in the process, the state of the polymeric ammonium salt, the solvent content of the polymer, the degree to which the polymer is swollen, and the improvement of overall process efficiency.
- particle size range polymeric ammonium salt particles.
- the solvent used for slurrying the polymer may be either a swelling or nonswelling solvent depending on the type of milling under consideration.
- size reduction is done in the damp or dry state it is possible for a combination drying-milling or purification-milling operation to be done.
- size reduction is done in the dry state, the polymer may be milled at several temperature ranges: cryogenic, such as liquid nitrogen or carbon dioxide; ambient; and elevated, up to -150° C (below temperatures which may cause significant
- the polymeric ammonium salt product of the present invention is preferably dried so as to remove solvent.
- drying is meant the removal of solvent from the polymer matrix. Methods commonly used by those skilled in the art of drying may be employed. Methods for drying include, but are not limited to, tray drying, spray drying, flash drying, tumble drying, rotary paddle drying (either vertical or horizontal, and/or agitated drying, wherein the polymer is exposed to heat, vacuum, and/or dry gas convection to effect the removal of solvent.
- polymeric ammonium salts When polymeric ammonium salts are wetted with higher boiling solvents, drying time is longer than when they are wetted with lower boiling solvents, and it may be desirable to perform a solvent displacement. For example, a polymeric ammonium salt wetted with water will take approximately five fold longer to dry than the same polymer wetted with methanol when the same drying method is employed.
- the solvent displacement may be accomplished by several means which include, but are not limited to, azeotropic distillation, direct
- azeotropic distillation will only work if the two solvents under consideration form an azeotrope.
- a water wetted polymeric ammonium salt may be azeotropically distilled in toluene to effect removal of the water.
- the polymeric ammonium salt wetted with the undesired solvent is placed in an apparatus which allows for the physical separation of solids and liquids, as described above.
- the second solvent is added to the already wetted polymer and after a suitable equilibration time, the solvents are removed. Repeated exposure of the wetted polymer to the desired solvent will eventually effect a displacement of the undesired solvent.
- water wetted polymeric ammonium salts placed in a filtration apparatus, would be treated with alcohol and allowed to equilibrate.
- the mother liquor would now contain both the desired and undesired solvent.
- a polymeric ammonium salt wetted with water, or other salt dissolving solvent is treated with an inorganic salt, either solid or dissolved in a solution, to effect a collapse of the polymer matrix with concommitant desolvation, i.e., the change in solvent dielectric constant, by the addition of salt, causes the polymer to collapse and squeeze out the undesired solvent.
- the degree to which the polymeric ammonium salt matrix collapses may be related to the concentration of salt in solution.
- Salts that may be used for salting out include, but are not limited to, metal halides, metal carbonates, metal phosphates, metal sulfates, and metal carboxylates . For example, when a water wetted polymeric ammonium salt is treated with NaCl, either solid or in solution, the polymer matrix
- the in vivo efficacy of polymeric crosslinked bile acid sequestrants may be improved by carrying out the gelation of the polymer (during the polymerization step described above) in the presence of a "sequestrant enhancer”, also referred to as “template” herein.
- a "sequestrant enhancer” also referred to as “template” herein.
- template means a chemical substance which is substantially inert to the reaction, reaction starting materials and products, and that effects an enhancement of the serum cholesterol lowering property of the polymer product.
- the present invention includes improved methods for the preparation of the crosslinked polymeric ammonium salt polymer (comprising Y and Z groups, as defined above) of the present invention, wherein the improvement comprises carrying out the polymerization and/or gelation step for the synthesis of such crosslinked polymeric ammonium salt polymer in the presence of a template, thereby to enhance the bile acid sequestrant properties of such crosslinked polymeric ammonium salt polymer.
- Templates, as described herein may be used in the polymerization and/or gelation process for the synthesis of other bile acid sequestrant polymers, other than the crosslinked polymeric ammonium salts of the present invention comprising Y and Z groups as described above.
- the present invention also includes improved methods for the preparation of other bile acid
- Such “other bile acid sequestrant polymer” includes, but is not limited to, colestipol hydrochloride and cholestyramine.
- Scanning electron micrographs of the crosslinked polymers of the invention prepared in the presence of the templates generally show a porous or reticulated structure with pore size ranging from about 1 to 300 microns depending on the overall particle size of the crosslinked polymer. This is in contrast to the appearance of the same crosslinked polymeric materials prepared in the absence of templates which exhibit essentially no porous structures.
- the templates should be added at the beginning of the crosslinking and/or polymerization reaction. Normally, the template will remain in the gel until it is removed, as by solvent extraction (as discussed above and further below) .
- the process for the synthesis of the uncrosslinked polymers of the invention is carried out in solution (until gelation occurs, at which time the bile acid sequestrant being formed becomes crosslinked and insoluble), in the sense that the starting materials which react to form the crosslinked polymer are in solution. If a template is used, it may be soluble, partially soluble, or insoluble in the reaction medium (the solvent and starting materials for the crosslinked polymer).
- the template should be soluble in a solvent (not necessarily the solvent used in the crosslinking process) so that it can be separated from the
- the template may be separated from the crosslinked polymer by extraction of the crosslinked polymer with a solvent in which the template is soluble.
- a solvent in which the template is soluble This can be the same solvent as used in the instant process if a soluble polymer is used as the template.
- Solvent extraction also encompasses use of a solvent as the extractant which chemically converts the enhancer to a soluble material, while not substantially affecting the polymer structure of the crosslinked polymer.
- an aqueous acid such as aqueous HCl
- HCl may also convert the polymeric ammonium salt to a chloride.
- the solvent used to remove the template from the crosslinked polymer of the invention may change the salt form of the crosslinked polymer.
- crosslinked polymeric bile acid sequestrant may, if desired, be isolated in pure form by removal of the extraction solvent, as by filtration and/or evaporation in air or under vacuum.
- Templates which are insoluble in the reaction medium may, preferably, have a particle size of less than about 1000 microns (measured as being able to pass through a sieve of that size), more preferably less than about 600 microns.
- particle sizes may be made, for example by grinding a solid substance, or by dispersing a liquid substance (including a polymer) in the solvent beforehand using high shear. Dispersion of the
- insoluble template during the process can be maintained by simple means, such as agitation.
- the template should not interfere in the
- the enhancer should also not strongly coordinate with any of the starting materials for the crosslinked polymeric bile acid sequestrant, or the crosslinked polymer itself.
- Polymers for use as templates include both natural and synthetic polymers, including both thermoplastics and elastomers.
- Useful polymers include, but are not limited, to polyacrylates, polymethacrylates, polyvinylpyrrolidone, poly(vinyl acetate), various starches, corn products such as amaizo, amylose and zein, pectin, alkoxylated celluloses, polyesters and polyethers.
- substances also include cellulose polymers (such as ethylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxypropylmethylcellulose), polyethylene glycol, proteins, nucleic acids, albumin, gelatin, starch, collagen, dextran and modified dextrans,
- polysaccharides polylactide/ polyglycolide, polyalkylcyanoacrylates, polyacrylamide, polysorbates,
- polyethylene ethers and esters polyethylene ethers and esters, and polyoxyethylene/polyoxypropylene block polymers .
- Suitable templates may also include natural and synthet ic gums (such as acacia, tragacanth, or sodium alginate), sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, agar, bentonite, xanthan gum, cholesterol, stearylamine, phospholipids (such as phosphatidylcholines), and soluble polymers such as polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
- natural and synthet ic gums such as acacia, tragacanth, or sodium alginate
- sodium oleate sodium stearate, magnesium stearate
- sodium benzoate sodium acetate
- agar bentonite
- xanthan gum cholesterol
- stearylamine phospho
- polymers useful as templates may include polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
- polydihydropyrans polycyanoacylates
- amphipathic block copolymers of hydrogels Preferred polymers include poly(2-hyroxyethyl methacrylate),
- Nonpolymeric templates include, but are not limited to: mono- or disaccharides, such as galactose, lactose, trehalose, and sucrose; steroid derivatives; cholesterol
- bile acid derivatives such as sodium cholate and methyl cholate
- inorganic materials and salts such as sodium and potassium halides (for example, KCl and NaCl), metal carbonates (preferably Li, K, and Na carbonates), borates and phosphates (and salts thereof).
- metal carboxylates such as acetates, propionates, butyrates, salicylates,
- gluconates ascorbates, citrates, and salts thereof.
- Inorganic material useful as a template in the present invention includes borates and phosphates (and salts thereof) in the form of monomeric salts or as polymeric forms, or as mixtures of monomeric and polymeric forms.
- the inorganic material may be in a crystalline and amorphous form, or a mixture thereof.
- Preferred lower molecular weight templates are trehalose, sodium chloride, methyl cholate and cholesteryl chloride.
- One or more of the above-described templates may be used in combination in a particular polymerization and/or gelation step for the synthesis of the
- crosslinked polymers of the present invention are crosslinked polymers of the present invention.
- the proportions of the various reaction ingredients (reactant starting materials, template, solvent) for the polymerization/gelation in the presence of template may be selected as described above for the polymeriziation step (as in the absence of template).
- the stoichiometry of the materials (i.e., monomers and/or polymers) which will form the crosslinked polymer may be important to obtaining the preferred desired crosslinked polymer, as it is in the absence of template, as described above.
- Useful proportion ranges of the template are 5 to 500 percent by weight (of the entire reaction mass) of template, 5 to 500 percent by weight of solvent and 5 to 500 percent by weight of the materials which will form the crosslinked polymer.
- the improved polymeric ammonium salts with enhanced bile acid binding properties which are prepared using a template, may be further processed as described above by purification, ion exchange, size reduction, and/or drying.
- the polymeric ammonium salts of the present invention are useful as bile acid sequestrants (which lower blood plasma cholesterol levels), moisture or solvent absorbents, electroconductive agents, charge transfer agents, chelating agents and ion exchange resins .
- compositions herein of the polymeric ammonium salts which are useful as bile acid sequestrants have a B max /K d value for cholate of greater than 0.75, more preferably 1.0 or more.
- B max is the maximum amount of bile acid (in this case cholate) bound per unit of crosslinked polymer of the invention, wherein Bmax is expressed in units of ⁇ mol of bile acid
- K d (in this case cholate) bound per mg of dry crosslinked polymer of the invention.
- Equation 1 concentration of free bile acid (in this case cholate) at which there is half-maximal binding of the bile acid to the crosslinked polymer of the invention.
- Kd is expressed in units of mM.
- the binding of bile acid to the crosslinked polymer of the invention may be measured using the procedures described herein below.
- the B max and Kd values are determined by best-fit regression fitting the binding data using either Equation 1 or Equation 2, below:
- Equation 1 where [Bound] and [Free] are the concentration of polymer-bound and free bile acid (in this case cholate), respectively, and n is a curve fitting parameter.
- Equation 2 The ligand-ligand interaction model isotherm that is used is represented by Equation 2 :
- Equation 2 where F is the free bile acid concentration; W is the ligand ligand interaction parameter or cooperativity parameter; and Sqrt is the square root of the quantity in brackets.
- a utility for the crosslinked polymeric ammonium salts of the present invention is as bile acid sequestrants for lowering blood plasma cholesterol in mammals.
- Coronary and peripheral vascular diseases are major problems in Western society and elevated blood cholesterol levels is one of the major risk factors in the development of atheroscherosis in animals as well as in humans.
- lipid-lowering agents have shown the beneficial effects of lowering cholesterol and low-density lipoprotein (LDL) cholesterol in the prevention of coronary heart disease.
- prodrugs refer to derivatives of the disclosed compounds made by modifying functional groups present in the compounds in such a way that the
- prodrug derivatives include, but are not limited to acetate, formate and benzoate derivatives and the like.
- the bile acid sequestrant polymers of the invention can be administered as cholesterol lowering agents by any means that produces contact of the active agent with bile acids in the gut of a mammal.
- the bile acid sequestrant polymers of the invention are preferably administered orally, and are administered either as individual therapeutic agents or in combination with other therapeutic agents, such as with other
- hypocholesterolemic agents and other drugs for the treatment of cardiovascular diseases can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis standard pharmaceutical practice.
- administered in combination or “combination therapy” it is meant that the crosslinked polymeric ammonium salt compound and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
- each component may be administered at the same time or sequentially in any order at different points in time.
- each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
- terapéuticaally effective amount it is meant an amount of a crosslinked polymeric ammonium salt of the invention that when administered to a mammal binds with bile acids in the intestinal tract of the mammal thereby to increase fecal loss of bile acids and preventing the absorption of the bile acids.
- the crosslinked polymeric ammonium salts of the invention when administered alone or in combination with an additional therapeutic agent to a mammal are effective to reduce blood serum cholesterol levels to prevent or ameliorate a hypercholesterolemia disease condition or the progression of the disease.
- the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
- the daily dosage of active will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
- the bile acid sequestrant polymers of the invention may be administered for a period of continuous therapy of one month or more, sufficient to achieve the required lowering in serum cholesterol levels.
- compositions suitable for injection compositions suitable for injection.
- compositions contain from about 0.1 gram to about 10 grams of active ingredient per unit .
- the active ingredient will ordinarily be present in an amount of about 20-95% by weight based on the total weight of the composition.
- the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
- solid dosage forms such as capsules, tablets, and powders
- liquid dosage forms such as elixirs, syrups, and suspensions.
- Formulation of dosage forms of the polymers of the present invention must take into account the swelling of the particular polymers by water or other solvents.
- the polymers of the invention can also be any polymers of the invention.
- the polymers of the invention can also be any polymers of the invention.
- the polymers of the invention may be administered in tablet or in gelatin capsules containing solid bile acid sequestrant polymer or an aqueous or semi-aqueous suspension of solid polymer containing a suitable suspending agent.
- Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastro-intestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are suitable stabilizing agents.
- solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
- compositions of the present invention can be prepared by techniques known to those skilled in the art of pharmacy. Suitable pharmaceutical carriers and formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
- Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 0.5 gram of powdered active
- Soft Gelatin Capsules A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.5 gram of the active ingredient. The capsules are washed and dried.
- a digestable oil such as soybean oil, cottonseed oil or olive oil
- Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 0.5 gram of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 0.5 gram of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase
- aqueous suspension is prepared for oral administration so that each dose contains
- crosslinked polymeric ammonium salt compounds of the present invention may be administered in any order.
- an inhibitor of acyl-coenzyme A cholesterol O-acyltransferase (ACAT); an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, such as lovastatin; a lipid regulating agent, such as
- the crosslinked polymeric ammonium salt compound of the present invention and such additional therapeutic agent can be administered separately or as a physical combination in a single oral dosage unit.
- the crosslinked polymeric ammonium salt compound of the present invention may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.).
- the crosslinked polymeric ammonium salt compound of the present invention and the second therapeutic agent may be administered essentially at the same time, or sequentially in any order.
- the dosage of the crosslinked polymeric ammonium salt compound when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic
- the proper dosage of the crosslinked polymeric ammonium salt compound when administered in combination with the second therapeutic agent will be readily ascertainable by a medical practitioner skilled in the art, once armed with the present disclosure.
- the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
- the present invention also includes pharmaceutical kits useful for the treatment of hypercholesterolemia, which comprise one or more containers containing pharmaceutical dosage units comprising a pharmaceutical composition comprising a therapeutically effective amount of a crosslinked polymeric ammonium salt compound of the present invention. Instructions, either as inserts or as labels, indicating quantities of the dosage units to be administered, guidelines for
- administration the dosage units, etc. may also be included in the kit.
- MeOH is methanol
- EtOH is ethanol
- DMAC is N,N-dimethylacetamide
- DMF is
- DBD is 1,10-dibromodecane
- HMD is 1,6-hexamethylenediamine
- the bromide counterion or any other counterion can readily be exchanged by exposing swollen wet (H 2 O) polymer to a 10% solution of ammonium hydroxide.
- the neutralized polymer shrinks (deswells) and is filtered and washed with water until the resulting filtrate is neutral to pH paper.
- the polymer is then reacidified with the appropriate acid to give the desired counter ion (e.g., HCl for Cl-ion; HOAc for acetate ion; etc.).
- the polymer swells again.
- the swollen polymer is then washed with water until the filtrate is neutral to pH paper and dried under vacuum to yield a granular polymer with a different counter ion .
- Examples 2-38, Table 1 were carried out in a similar manner to Example 1A. Reflux and heating times were the same as in Example 1A.
- DMAC N,N-dimethylacetamide
- HPC hydroxypropylcellulose 85,000 MW.
- the speed of the agitator was set to 90 rpm.
- the material was heated to 60°C for one hour with an external circulating heater to dissolve the HPC.
- the solution was cooled to 40°C and 54 g of hexamethylene diamine and 26.8 g of sodium carbonate added.
- the solution of DBD in the solvent mixture was added over a period of 30 minutes at a constant rate using a piston pump, maintaining the temperature at 40°C, followed by the ten mL of solvent mixture saved for a rinse.
- the temperature of the reaction mixture was raised by 10°C every 15 min until the temperature was 80°C.
- the polymer gel (crumb-like solid) was cooled to 25°C and 2000 mL water and 65.8 g of 50% NaOH were charged to give a final pH of 12.2. After agitating for one hour the slurry was divided into three equal parts. An additional 500 mL of water was added to one third of the slurry and filtered using vacuum. The cake was washed with 400 mL water.
- the cake was slurried in 1000 mL water and
- the wet cake was dried in a small glass rotary dryer to yield 118.5 g or 74% theoretical yield based on the weight of the monomers charged.
- the swell of the dried polymer was 16.
- the gel was then put into a blender with an equal volume of 10% aqueous ammonium hydroxide and was ground in the blender.
- the resulting polymer was filtered and then slurried in 10% aqueous ammonium hydroxide for 1 hour.
- the polymer was then filtered and washed with distilled water until the filtrate was neutral.
- the polymer was then treated with 10 L of aqueous HCl (4 L cone. HCl + 6 L water).
- the polymer was then filtered and washed with distilled water until the filtrate was neutral.
- the polymer was then washed with methanol and slurried in methanol.
- the slurried polymer was then loaded into 5 L Soxhlet extraction thimbles and extracted with methanol for 3-4 days and with water for an additional 3-4 days.
- the polymer was then removed from the extraction thimbles and dried in a vacuum oven at 60°C for 2-3 days to yield the final polyammonium product containing chloride counter ion.
- Theoretical yield was 1089 g.
- Yield before extraction was 823 g.
- Yield after extraction was 800 g.
- the polymer could be ground in a blender or coffee mill to yield particle sizes of
- the transfer line was flushed with an additional 0.4 kg of DMAC and 0.4 kg of methanol.
- the mixer/reactor was held at 35 ⁇ 5°C for 15 minutes after the transfer. Then the jacket outlet temperature was raised to 80°C over 4 hours. The plow speed was reduced to 40 rpm when the outlet temperature reached 80°C.
- the horizontal mixer/reactor jacket outlet was maintained at 80°C for another 16 hours.
- the wet milled material was transfered to a glass-line agitated vessel.
- a glass-line agitated vessel To the vessel containing the slurry 27.6 kg of 27% aqueous ammonium hydroxide was added. The mixture was heated to 50°C. After it reached 50°C it was filter on an agitated filter.
- the filter media consisted of three 316 stainless steel screens. A 38 micron screen was the primary filtration layer. The two other screens, which were 150 micron or larger, provided support.
- the wetcake in the filter was reslurried and filtered consecutively with 36 liters of USP water, a mixture of 44.5 kg of USP water and 5.4 kg of 27% ammonium hydroxide, 36 liters of USP water, a mixture of 44.5 kg of USP water and 5.4 kg of 27% ammonium hydroxide, and 36 liters of USP water. All reslurries and filtrations were done at 50 °C.
- the wetcake from the initial quench was split in four parts each part was treated separately as described below.
- each part was treated successively with acid, base, acid, base and acid.
- wetcake was reslurried in the agitated filter in 84 liters of USP water. Enough 32% aqueous HCL was added to lower the pH to less than 2.5.
- wetcake was reslurried in the agitated filter in 45 liters of USP water. Enough 27% aqueous ammonium hydroxide was added to raise the pH to greater than 9.5.
- After each base treatment the wetcake was washed with 36 liters of USP water.
- For the final acid treatment the pH was lower to 1.5 vs. the typical 2.5.
- the wetcake from the final acid treatment was washed until the pH was above 3.5. A total of 148.8 kg of wetcake was recovered from purification.
- the same milling apparatus used for initial milling was used for final milling except the heads of the inline continuous flow through mill were changed. A fine and two superfine heads were installed.
- the 4 lots of wetcake recovered from purification were combined and milled in two lots. Each lot was was slurried in USP water prior to milling. For each kg of wetcake 0.5 kg of USP water was added. The slurry was milled for approximately 4 hours to get the particle size to 60-70 microns (50 percentile) . Drying The two lots of wetmilled slurry were dried in a rotary vacuum dryer with 1.1 cubic feet of working capacity. Hot water (80-90°C) was aligned to the dryer jacket. Vacuum (22-26 inches of Hg) was aligned to the drying chamber. Drying took approximately 5 days to complete. 11.3 kg of dry polymer product was recovered. The swell of the product polymer was 13.0-13.6.
- Example 1A was added 13 mL of distilled water. Within minutes the polymer swelled to completely absorb that volume of water. When the vial was inverted no liquid water poured. This behavior indicates at least a 26:1 (2600%) swell factor for this polymer.
- Example 1A was placed in a 10 mm NMR tube. To this was added deuterated water (D 2 O, 1.0 g) to swell the polymer. Dioxane (1.8 g) was then added to slurry the polymer and a 13 C NMR spectrum was acquired on the sample using a Varian VXR-400 S spectrometer and the following settings: 100.577 MHz sfrq, 80 deg. flip angle, 2.300 sec. aquisition time, 18.622 sec. delay, 31948.9 Hz sweep width, 2800 transients, 20 °C probe temperature, 5 Hz line broadening, Waltz decoupling, and coupler gated off during delay.
- D 2 O deuterated water
- Dioxane 1.8 g
- this polymer contained 53.6% secondary (straight chain) amines, 24.0% tertiary amines as either branch points or crosslinks, 21.0% primary amines as ends, and 1.3% quaternary amines as crosslinks or branch points.
- the reproducibility of the above-described method is about ⁇ 5% of a given value, i.e. 53.6 ⁇ 2.5 %, 24.0 ⁇ 1.2 %, and 21.0 ⁇ 1.0 %.
- the above-described method may be used to determine the nitrogen abundances for the polymers of the present invention.
- sequestrant crosslinked polymeric ammonium salts of the present invention may be measured using the procedures described below.
- the following method was used to measure the equilibrium binding paramaters for the binding of various bile acids to the bile acid sequestrants of the present invention.
- the equilibrium binding of bile acids to bile acid sequestrants was determined using isotonic ionic conditions at 37°C, in order to roughly approximate physiological conditions.
- Carbon-14 ( 14 C) labeled bile acids dissolved in phosphate buffered saline (PBS) at pH 7 were prepared at 0.454, 0.555, 0.713, 1.000, 1.667, 5.000, 6.667, 10.0, 20.0 and
- the bile acids were purchased from Sigma (St.
- bile acid sequestrant Two mL of the prepared concentrations of bile acid were added to a selected amount (for example, 5.0 mg) of bile acid sequestrant to be tested, within a 10,000 mw cut-off ultrafiltration cup (Nihon Millipore, Yonezawa, Japan) and incubated overnight (16 hours) at 37°C.
- Cholestyramine which was tested for reference, was obtained from Sigma, St. Louis, MO.
- the ultra-filtration cups were centrifuged at 3,500 RPM at 37°C in a Du Pont RT6000 centrifuge to pass the solution of free bile acids into the outer tube.
- Two hundred ⁇ L of the separated binding tubes and the corresponding set of the stock solutions of total bile acid were counted for two minutes in a beta scintillation counter (Beckman, Palo Alto, CA) to detect 14 C DPMs in 7 mL of Formula 989 scintillation cocktail (E. I. du Pont de Nemours and Company, New England Nuclear, Billerica, MA).
- the respective specific bound DPMs were determined from the counted total added 14 C DPMs and derived total binding and non-specific binding DPMs.
- the specific bound DPMs were converted to specifically bound ⁇ moles of bile salts at each dose level.
- the specific binding data was plotted on a saturation binding curve (specific bound ⁇ moles of bile salts/mg of sequestrant versus the log of the free ⁇ moles of bile salts/mL of solution) and the best-fit regression curve was determined using the relationship, Equation 1 below:
- Equation 1 Equation 1 where Bmax is the maximum amount of bile salt bound to sequestrant, Kd is the concentration of free bile salt at which there is half-maximal binding (i.e., an
- Equation 2 Equation 2
- Equation 2 where F is the free bile acid concentration; W is the ligand ligand interaction parameter or cooperativity parameter; and Sqrt is the square root of the quantity in brackets.
- the value B max /K d is a measure of the binding efficiency of the bile acid sequestrant for the binding of bile acids, and reflects both the total number of binding sites or binding capacity and the binding affinity of the bile acid sequestrant for bile acid. The higher this number is, the more effective a bile acid sequestrant is predicted to be.
- sequestrant polymers of the present invention are substantially more effective in binding bile acids, in terms of both increased affinity and increased binding capacity, relative to cholestyramine.
- bile acid sequestrant polymers of the present invention is shown in Table 5 below. Male hamsters were fed for 2 weeks the selected bile acid sequestrant to be tested and the total cholesterol concentration in the plasma was determined. Total serum cholesterol was measured using a cholesterol oxidase assay on a Dimension ® clinical analyzer.
- sequestrants were given orally by mixing in the animal feed.
- the hamsters were given 11 g of Agway rodent chow per day for 2 weeks that contained varying weights of sequestrant. Results for 0.25, or 0.3 weight %
- sequestrant for example 0.3 weight % is 0.033 g sequestrant per 11 g of feed are shown.
- the polymer was ground and mixed with the feed.
- the uncertainty in the measured cholesterol lowering is expressed as the SEM (or standard deviation (SD)) for a particular study (i.e., for 7 animals).
- SEM standard deviation
- the SEM (or SD) for the study at Week 0 and Week 2 is given and the SEM (or SD) is also expressed as a % of the average value of total cholesterol. Also given in Table 5 is the % decrease in total cholesterol level and the average % SEM (or SD) for Weeks 0 and 2.
- the total cholesterol levels are the average values for 7 animals .
- the value following ⁇ is the standard error of the mean (SEM) except where marked with asterisk ( * ) , where it is a standard deviation (SD) .
- the cholesterol lowering efficacy of the polymer of Example 25 was tested in male New Zealand rabbits. As shown in Table 6 below, following 1 week and 2 weeks of treatment of rabbits with this polymer at 250 mg/kg of total body weight per day, the plasma total cholesterol levels in the animals were significantly decreased.
- Table 6 shows the mean % decrease in total plasma cholesterol levels for 5 animals (the SEM is given following ⁇ ).
- the bile acid sequestrant was
- Total serum cholesterol was measured using a cholesterol oxidase assay on a
- Sequestrant polymers were made by a procedure similar to that used in Example 1A.
- the starting materials and synthesis conditions are given in Table 7.
- Each polymer was weighed directly into a Millipore® ultra filtration cup (10,000 NML low binding cellulose). The weight added to each cup was around 5 mg/cup with the actual weight being recorded and each polymer was weighed into 3 cups.
- a 10 mM glycocholic acid solution (GC) was made with phosphate buffered saline (PBS) at a pH of 7, and kept at 37°C. To each cup, 2 ml of the above solution was added. This was done in sets of no more than 15 cups. Once the bile acid was added to the cups the cups were mixed with a vortex mixer and placed in a centrifuge. The cups were spun in a Sorvall®
- each polymer was weighed directly into the Millipore ultra filtration cups (10,000 NML low binding cellulose). The weight added to each cup was around 5 mg/cup with the actual weight being recorded and each polymer was weighed into 3 cups.
- a 10 mM glycocholic acid solution (GC) was made with phosphate buffered saline (PBS) at a pH of 7. To each cup, 2 mL of the above solution was added. The cups were incubated in an orbital dry air shaker at 37°C for between 18 to 20 hours. After incubation the cups were spun in the Sorvall RT6000 centrifuge at 3500 RPMS (setting #10) at 37°C for 1 hour or until at least 200 ⁇ l of solution had been eluted.
- PBS phosphate buffered saline
- the reagents were bought as a kit from Sigma Chemical Co., St. Louis, MO 63178, Bile Acid Diagnostic Kit #450-A. Reagents were gently reconstituted with water, 10 ml for reagent A and 5 ml for reagent B. They were mixed by inverting, not shaking. The test reagent was maded by mixing reagent A with reagent B at a volume ratio of 4:1. For each sample 0.5 ml of the test reagent was needed. The test reagent was warmed to 37°C by placing it in a 37°C water bath about 15 minutes before it was needed. The assay was performed in 6 ml polypropylene test tubes. Each sample was diluted so as to be in the linear range of the assay.
- the bile acid salt filtrate samples and the 10 mM GC were first diluted 10 times, 100 ⁇ l plus 900 ⁇ l PBS. Each sample was done in duplicate so that for each example there were six samples. PBS was used as a zero control and the Absorbance from the average of 6 PBS samples was subtracted from all other samples.
- the 10 mM GC was diluted by a total factor of 50 to be at the maximum range of the assay, which is 200 ⁇ M, and six samples were tested. The samples were diluted by a total factor of 40. Two hundred ⁇ l of sample was needed for the assay. Since the samples were first diluted by 10 then diluted by 4, 50 ⁇ l of diluted sample plus 150 ⁇ l of PBS was assayed.
- bile acid sequestrants were made in the presence of templates B max and K d were determined by the ligand-ligand method of Equation 2, as in Table 4. Percent in vitro binding (of glycocholate) was determined the same way as for Table 8.
- the stirrer was then stopped and the polymer was allowed to stand at 35°C overnight.
- the polymer was then removed from the flask and ground in a blender with an equal volume of 10% ammonium hydroxide. After filtration and washing, the polymer was slurried in 10% ammonium hydroxide for one hour. It was then filtered and washed until neutral, and then slurried in 100 mL 4N HCl for about 30 minutes. The polymer was filtered and again washed until neutral, giving a swollen gel. The gel was purified by
- Residual HPC could be monitored in the final polymer by IR (bands at -1080 cm -1 for HPC) and C-13 NMR (broad peak -75-80 ppm). If a thorough wash is
- the reaction mixture formed a slurried gel after -30 minutes.
- the stirring rate was reduced and the flask heated for an additional 6 hours.
- the contents of the flask were then mixed with aqueous ammonium hydroxide and agitated for an hour at room temperature.
- the polymer was then filtered and washed with water repeatedly.
- the polymer was then transferred to a large beaker and stirred with aqueous hydrochloric acid for about 30 minutes.
- the polymer was then filtered and washed with water
- HPC hydroxypropyl cellulose
- the polymer was then washed with water and reacidified with aqueous HCl.
- the gel was again washed with water and extracted in a Soxhlet apparatus first with methanol for 3 days and then with water for 3 days.
- the polymer was then dried in a nitrogen purged vacuum oven at 60°C and ground in a coffee mill to yield 14.6 g of desired product.
- the swell measured 14.9 in water and in vitro binding of glycocholate was 79.4%.
- Examples 81-97 were prepared in essentially the same manner as Example 74 except that the quantities used were l/20th of those used in the original example (e.g., 12 mL of methanol, 12 mL of DMF, 3.86 g of hexamethylenediamine, and 10 g of 1,10-dibromodecane).
- the template and the quantity of template used are shown in Table 9 along with the resulting swell and in vitro glycocholate binding data (10 min. test) :
- control was a polymer prepared in the same manner as
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Abstract
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Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
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BR9506636A BR9506636A (en) | 1994-01-18 | 1995-01-18 | Process for preparing a crosslinked polymeric ammonium salt gel or polymeric amine gel Process for preparing a crosslinked polymeric ammonium salt method for reducing blood plasma cholesterol levels in a mammalian method for sequestering bile acids salt gel product polymeric ammonium and pharmaceutical composition |
CZ961943A CZ194396A3 (en) | 1994-01-18 | 1995-01-18 | Process for preparing cross-linked gels of polymer ammonium salts |
NZ279647A NZ279647A (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric amine/ammonium gels |
PL95315580A PL315580A1 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
SK936-96A SK93696A3 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
EP95908568A EP0740679B1 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
JP7519211A JPH09507687A (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salt |
AU16834/95A AU682930B2 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
DK95908568T DK0740679T3 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
CA002179712A CA2179712C (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
AT95908568T ATE204005T1 (en) | 1994-01-18 | 1995-01-18 | CROSS-LINKED POLYMERIC AMMONIUM SALTS |
MX9602812A MX9602812A (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts. |
DE69522095T DE69522095T2 (en) | 1994-01-18 | 1995-01-18 | NETWORKED POLYMERIC AMMONIUM SALTS |
KR1019960703844A KR970700714A (en) | 1994-01-18 | 1996-07-16 | CROSSLINKED POLYMERIC AMMONIUM SALTS |
NO962985A NO962985L (en) | 1994-01-18 | 1996-07-17 | Crosslinked polymeric ammonium salts |
FI962881A FI962881A (en) | 1994-01-18 | 1996-07-17 | Crosslinked polymeric ammonium salts |
GR20010401446T GR3036589T3 (en) | 1994-01-18 | 2001-09-11 | Crosslinked polymeric ammonium salts |
Applications Claiming Priority (4)
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US18295494A | 1994-01-18 | 1994-01-18 | |
US08/182,954 | 1994-02-24 | ||
US08/202,395 US5556619A (en) | 1992-08-20 | 1994-02-24 | Crosslinked polymeric ammonium salts |
US08/202,395 | 1994-02-24 |
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WO1995019384A1 true WO1995019384A1 (en) | 1995-07-20 |
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PCT/US1995/000713 WO1995019384A1 (en) | 1994-01-18 | 1995-01-18 | Crosslinked polymeric ammonium salts |
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US (2) | US5556619A (en) |
EP (1) | EP0740679B1 (en) |
JP (1) | JPH09507687A (en) |
KR (1) | KR970700714A (en) |
CN (1) | CN1143379A (en) |
AT (1) | ATE204005T1 (en) |
AU (1) | AU682930B2 (en) |
BR (1) | BR9506636A (en) |
CA (1) | CA2179712C (en) |
CZ (1) | CZ194396A3 (en) |
DE (1) | DE69522095T2 (en) |
DK (1) | DK0740679T3 (en) |
ES (1) | ES2160696T3 (en) |
FI (1) | FI962881A (en) |
GR (1) | GR3036589T3 (en) |
HR (1) | HRP950024A2 (en) |
HU (1) | HUT75944A (en) |
IL (1) | IL112343A0 (en) |
NO (1) | NO962985L (en) |
NZ (1) | NZ279647A (en) |
PL (1) | PL315580A1 (en) |
PT (1) | PT740679E (en) |
SK (1) | SK93696A3 (en) |
WO (1) | WO1995019384A1 (en) |
Cited By (6)
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WO1998043653A1 (en) * | 1997-03-27 | 1998-10-08 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
WO2000038664A2 (en) * | 1998-12-23 | 2000-07-06 | Geltex Pharmaceuticals, Inc. | Amine condensation polymer bile acid sequestrants |
USRE41316E1 (en) | 2004-03-22 | 2010-05-04 | Han Ting Chang | Crosslinked amine polymers |
US7718746B2 (en) | 2003-11-03 | 2010-05-18 | Ilypsa, Inc. | Anion-binding polymers and uses thereof |
US7767768B2 (en) | 2003-11-03 | 2010-08-03 | Ilypsa, Inc. | Crosslinked amine polymers |
US10272103B2 (en) | 2010-02-24 | 2019-04-30 | Relypsa, Inc. | Crosslinked polyvinylamine, polyallylamine, and polyethyleneimine for use as bile acid sequestrants |
Families Citing this family (10)
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MX9602812A (en) * | 1994-01-18 | 1997-06-28 | Du Pont | Crosslinked polymeric ammonium salts. |
US6083497A (en) * | 1997-11-05 | 2000-07-04 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with unsubstituted polydiallylamine polymers |
US6271264B1 (en) * | 1998-12-01 | 2001-08-07 | Geltex Pharmaceuticals, Inc. | Polymers containing spirobicyclic ammonium moieties as bile acid sequestrants |
US6649187B2 (en) | 2001-02-16 | 2003-11-18 | Bristol-Myers Squibb Pharma Company | Use of polyalkylamine polymers in controlled release devices |
WO2005028528A1 (en) * | 2003-09-23 | 2005-03-31 | Akciju Sabiedriba 'olainfarm' | 3,5-dimethyl-1-adamantyl-ammonium polymeric salts and the use thereof in the form of antiviral agents |
JP5553421B2 (en) * | 2011-08-01 | 2014-07-16 | 株式会社ルネッサンス・エナジー・リサーチ | CO2-facilitated transport membrane and method for producing the same |
ES2590145T3 (en) | 2011-11-25 | 2016-11-18 | Basf Se | Lipophilic polyalkylene polyamines by homogeneously catalyzed alcohol amination |
KR101631151B1 (en) * | 2014-05-22 | 2016-06-27 | 한국과학기술연구원 | Method for synthesizing hydrocarbon electrolytes polymer and polymerization solvent used therein |
ES2857177T3 (en) * | 2014-12-10 | 2021-09-28 | Tricida Inc | Proton-binding polymers for oral administration |
CN113583256B (en) * | 2021-07-05 | 2022-10-25 | 南京理工大学 | Preparation method of cationic hydrogel material |
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1995
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- 1995-01-18 BR BR9506636A patent/BR9506636A/en not_active Application Discontinuation
- 1995-01-18 DK DK95908568T patent/DK0740679T3/en active
- 1995-01-18 AU AU16834/95A patent/AU682930B2/en not_active Ceased
- 1995-01-18 ES ES95908568T patent/ES2160696T3/en not_active Expired - Lifetime
- 1995-01-18 CN CN95191992A patent/CN1143379A/en active Pending
- 1995-01-18 DE DE69522095T patent/DE69522095T2/en not_active Expired - Lifetime
- 1995-01-18 CZ CZ961943A patent/CZ194396A3/en unknown
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- 1995-01-18 NZ NZ279647A patent/NZ279647A/en unknown
- 1995-01-18 CA CA002179712A patent/CA2179712C/en not_active Expired - Fee Related
- 1995-01-18 WO PCT/US1995/000713 patent/WO1995019384A1/en not_active Application Discontinuation
- 1995-01-18 JP JP7519211A patent/JPH09507687A/en active Pending
- 1995-01-18 SK SK936-96A patent/SK93696A3/en unknown
- 1995-01-18 EP EP95908568A patent/EP0740679B1/en not_active Expired - Lifetime
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- 1995-01-18 PL PL95315580A patent/PL315580A1/en unknown
- 1995-01-18 PT PT95908568T patent/PT740679E/en unknown
- 1995-01-18 AT AT95908568T patent/ATE204005T1/en not_active IP Right Cessation
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1996
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998043653A1 (en) * | 1997-03-27 | 1998-10-08 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
WO2000038664A2 (en) * | 1998-12-23 | 2000-07-06 | Geltex Pharmaceuticals, Inc. | Amine condensation polymer bile acid sequestrants |
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US7718746B2 (en) | 2003-11-03 | 2010-05-18 | Ilypsa, Inc. | Anion-binding polymers and uses thereof |
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USRE41316E1 (en) | 2004-03-22 | 2010-05-04 | Han Ting Chang | Crosslinked amine polymers |
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US8349305B2 (en) | 2004-03-22 | 2013-01-08 | Ilypsa, Inc. | Crosslinked amine polymers |
US10272103B2 (en) | 2010-02-24 | 2019-04-30 | Relypsa, Inc. | Crosslinked polyvinylamine, polyallylamine, and polyethyleneimine for use as bile acid sequestrants |
Also Published As
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NO962985D0 (en) | 1996-07-17 |
CA2179712A1 (en) | 1995-07-20 |
US5556619A (en) | 1996-09-17 |
HRP950024A2 (en) | 1997-06-30 |
FI962881A0 (en) | 1996-07-17 |
KR970700714A (en) | 1997-02-12 |
SK93696A3 (en) | 1997-04-09 |
CA2179712C (en) | 2001-11-27 |
PL315580A1 (en) | 1996-11-12 |
CN1143379A (en) | 1997-02-19 |
NZ279647A (en) | 1998-06-26 |
AU1683495A (en) | 1995-08-01 |
HU9601950D0 (en) | 1996-09-30 |
DK0740679T3 (en) | 2001-10-22 |
IL112343A0 (en) | 1995-03-30 |
AU682930B2 (en) | 1997-10-23 |
BR9506636A (en) | 1997-09-16 |
ATE204005T1 (en) | 2001-08-15 |
DE69522095T2 (en) | 2002-03-28 |
US5726284A (en) | 1998-03-10 |
ES2160696T3 (en) | 2001-11-16 |
GR3036589T3 (en) | 2001-12-31 |
EP0740679A1 (en) | 1996-11-06 |
DE69522095D1 (en) | 2001-09-13 |
PT740679E (en) | 2001-11-30 |
NO962985L (en) | 1996-09-17 |
EP0740679B1 (en) | 2001-08-08 |
JPH09507687A (en) | 1997-08-05 |
CZ194396A3 (en) | 1997-07-16 |
HUT75944A (en) | 1997-05-28 |
FI962881A (en) | 1996-07-17 |
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