CA2008114A1 - Alkylated polyethylenimine derivatives, process for their preparation, their use as pharmaceuticals and pharmaceutical preparation - Google Patents
Alkylated polyethylenimine derivatives, process for their preparation, their use as pharmaceuticals and pharmaceutical preparationInfo
- Publication number
- CA2008114A1 CA2008114A1 CA002008114A CA2008114A CA2008114A1 CA 2008114 A1 CA2008114 A1 CA 2008114A1 CA 002008114 A CA002008114 A CA 002008114A CA 2008114 A CA2008114 A CA 2008114A CA 2008114 A1 CA2008114 A1 CA 2008114A1
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- Prior art keywords
- crosslinked
- polyethylenimine
- alkylated
- carbon atoms
- agent
- 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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Classifications
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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
- C08G73/0206—Polyalkylene(poly)amines
- C08G73/0213—Preparatory process
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
- A23L3/3481—Organic compounds containing oxygen
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
- A23L3/3535—Organic compounds containing sulfur
-
- 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
Abstract
Abstract of the disclosure: HOE 89/F 018 Alkylated polyethylenimine derivatives, process for their preparation, their use as pharmaceuticals and pharmaceut-ical preparations Novel non-crosslinked and crosslinked alkylated poly-ethylenimines are described which can be used as hypo-lipidemic agents in the light of their bile acid-bind-ing activity. A process for the preparation of the said polyethylenimines and pharmaceutical preparations are also described.
Description
~1)8 I~OEC}`IST ~KTIENGESELLSC~T HOE B9/F 018 Dr. D/rh Description Alkyl~ted polyethylenimine derivatives, process or their preparation, their use as pharmaceuticals and pharmaceut-ical preparations The invention relates to alkylated polyethylenLmi~e derivatives, to a process for their preparation, to pharmaceutical preparations based on these compounds and to their use as pharmaceuticals, in particular for lowering increased lipid levels.
Insoluble basic, crosslinked pol~ners have been used for a considerable time for binding bile acid and are used therapeutically in the light of these properties.
Chologenic diarrhea (for example after resection of the ileum) and increased cholesterol blood levels are treated causally as the ob~ect of therapy. In the latter case, it is a matter of intervention in the enterohepatic circul~
ation, the corresponding resynthesis of cholesterol in the liver being provoked in place of the bile acid com-ponent taken out of the circulati.on. Recourse is made tothe circulating LDL (low density lipoprotein) cholesterol to meet the cholesterol need in the liver, the hepatic ~DL receptors coming into effect in increased number. The acceleration o~ LDL catabolism thus caused has an effect owing to the reduction of the atherogenic cholesterol content in the blood.
The ion exchangers used as pharmaceuticals have either quaternary ammonium groups (such as colestyramine) or secondary or tertiary amine groups (such as colestipol) as active gro~ps. The daily dose of colestyramine is expediently 12-24 g, and 32 g are recommended as the highest daily dose. 15-30 g is the recommended daily colestipol dose. Taste, odor and high dosage make patient compliance more difficult. The side effects go back to lack of selectivity (for example avi~aminoses), which even have to be considered in the dosage of medica~ents given ~imultan00usly~ and also to bile acid depletion, which cause variou~_ gastrointestinal disturbances ~co-nstipa~ion, steatorrhea~ to a different degree. For both preparations, a therapeutic significance by comhination with other hypolipidemis phannaceuticals such as fibr-ates, ~MG-CoA reductase inhibitors, probucol (cf., for example, M.N. CAYEN, Pharmac. ~her. 29, 187 ~1985) and 8th International Sympo3ium on Atharoscl~rosis, Rome, Oct. 9-13, 1988, Abstracts p. 544, 608, 710) has been described, the effects obtained even making the therapy of severe hyperlipidemia possible. It thexefore appears significant o find suitable subs~ances with the given principle of action and without the disadYantages of the preparations presently used.
- The following features of ~he preparations mentioned and, in particular, of colestipol are regarded as worthy of improvement:
1. The high daily doses, which are to be put down to a relatively low binding rate! at neutral pH in i60-tonic medium and the release ~ tial) o~ the adsorbed bile acid again.
Insoluble basic, crosslinked pol~ners have been used for a considerable time for binding bile acid and are used therapeutically in the light of these properties.
Chologenic diarrhea (for example after resection of the ileum) and increased cholesterol blood levels are treated causally as the ob~ect of therapy. In the latter case, it is a matter of intervention in the enterohepatic circul~
ation, the corresponding resynthesis of cholesterol in the liver being provoked in place of the bile acid com-ponent taken out of the circulati.on. Recourse is made tothe circulating LDL (low density lipoprotein) cholesterol to meet the cholesterol need in the liver, the hepatic ~DL receptors coming into effect in increased number. The acceleration o~ LDL catabolism thus caused has an effect owing to the reduction of the atherogenic cholesterol content in the blood.
The ion exchangers used as pharmaceuticals have either quaternary ammonium groups (such as colestyramine) or secondary or tertiary amine groups (such as colestipol) as active gro~ps. The daily dose of colestyramine is expediently 12-24 g, and 32 g are recommended as the highest daily dose. 15-30 g is the recommended daily colestipol dose. Taste, odor and high dosage make patient compliance more difficult. The side effects go back to lack of selectivity (for example avi~aminoses), which even have to be considered in the dosage of medica~ents given ~imultan00usly~ and also to bile acid depletion, which cause variou~_ gastrointestinal disturbances ~co-nstipa~ion, steatorrhea~ to a different degree. For both preparations, a therapeutic significance by comhination with other hypolipidemis phannaceuticals such as fibr-ates, ~MG-CoA reductase inhibitors, probucol (cf., for example, M.N. CAYEN, Pharmac. ~her. 29, 187 ~1985) and 8th International Sympo3ium on Atharoscl~rosis, Rome, Oct. 9-13, 1988, Abstracts p. 544, 608, 710) has been described, the effects obtained even making the therapy of severe hyperlipidemia possible. It thexefore appears significant o find suitable subs~ances with the given principle of action and without the disadYantages of the preparations presently used.
- The following features of ~he preparations mentioned and, in particular, of colestipol are regarded as worthy of improvement:
1. The high daily doses, which are to be put down to a relatively low binding rate! at neutral pH in i60-tonic medium and the release ~ tial) o~ the adsorbed bile acid again.
2. The gualitative shift in the bile acid composition of ~he bile with a decreasing tendency for cheno-deoxycholic acid and the increasing risk of chole-lithiasis associated with this.
3. The lack of a damping effect on the cholesterol metabolism of the intestinal bacteria 4. The binding rate of vitamins and pharmaceuticals, which is too high, makes a need for sub~titution of these substances and for blood level controls necessary in some cases.
5. A further improvement can be obtained in the form for administration.
The removal of the~ dsficiencies listed is surprisingly achieved by the use of hiqh molecular weight alkyla~ed polyethylenimines. The non-absorbable macromolecules exhibi~ their action both in soluble form, corre~ponding to the non-crosslinked structure, and in the insoluble state as the crosslinked polymer.
Crosslinked polyethylenimines are described in ~5 Patent 3,332,841. The crosslinking is carried out, inter alia, by means of alkylene groups having 2 to 8 carbon atoms, the molecular weight of the gtarting polymers being between 800 and 100,000. For the txeatment of temporary hyperacidity of the stomach, 0.25 to 5 g are administered per dosage unit. Neither the bincling of bile acid nor lS a lipid-lowering activity of the crosslinked polyethylen-~mines associated with this is described, as without alkylation the polyethylenimines have no binding capacity or only an insignificant binding capacity compared to the gallic acids, depending on the t~e. Owing to the lar~e potential ~harge density, provision can be mada for sufficient binding capacity by means of alkylation and for affinity and binding ~pecificity by means of ~he choice of substituents of appropriate hydrophilic/hydro-phobic character.
The invention therefore relates to non-crosslinked an~
crosslinked alkylated polyethylenimines, wherein ~he starting polyethylenimine has a molecular weight of lO,OOQ to lQ,000,000, the alkylating agent has the formula I
R-X (I) in which X is chlorine~ bromine, iodine, CH3-SO2 O- or ~H3 ~ SO2-O and R is a ~trai~ht-chain or branched Cl-C30-alkyl radical which is optionally substituted by a mono-or bicyclic saturated hyd:rocarbon having 5 to 10 ring carbon atoms, or by a phenyl radical and, in the case of the crosslinked alkylated polyethyl enimines, the crosslinking a~ent is an ~ dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms.
The process for the preparation of the alkylated poly-ethylenimine derivatives accordinq to the invention comprises alkylating a polyethylenimine having a molec-ular weight between 10,000 and 10,000,000 with an alkyl-ating agent of the formula R-X, in which X and R have the meanings indicated, and, if desired, crosslinking with an ~,~-dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms by - me~hods customary in polymer chemistry.
The crosslinking can be carried out before or after the alkylation. Carrying out the crosslinking and the alkyl-ation simultaneously is particularly prefPrred.
Polyethylenimines having a molecular weight above 100,000 are preferably employed.
In the alkylating agents R-X, X is preferably chlorine or bromine.
R is preferably a primary alkyl radical. If the alkyl radicals are substituted by the ring systems mentioned, these are preferably arranged so that they are linked to the polyethylenimine via a spacer having 1 to 4 CH2 yroups. The cyclohexyl radical is particularly suitable as a monocyclic saturated substituent. A suitable bi-cyclic hydrocarbon radical is, for exampleO decalin. A
particularly suitable alkylating a~ent, whose alkyl radical is substituted by phenyl, is benzyl bromide. A
suitable alkylating agent without substituents in the alkyl radical is preferably butyl chloride.
2~8~ ~
The alkylation can be carried out ~n ~everal stage~O In this way, the po~ibility axi~lt~ of fixing different substituent~ to tha same polymer.
The ratio of the alkylating agent employed to the amino groups of the polyethylenimine is 0.2:1 to 5:1, preferab-ly 0.5:1 to 2:1.
By means of the reaction with alkylating agents, a part cf the secondary amino groups in the chain are converted into tertiary and quaternary structures. The foxmation of tertiary amino groups is preferred.
Suitable crosslinking agent~ are, for example, di- and trihaloalkanes, preferably Q,~-dihaloalkanes such as, for - ex~mple, 1,6-dibromohexane and l,10-dibromodecane. The ~mount of the crosslin~er is preferably 2-25 mol-%, relative to the alkylating agent employed.
The alkylated polyethylenimines according to the inven-tion adsorb acids intrinsic to the body, in particul~r gallic acid. In the light of the~3e pxoperties, they are in a position to lower elevated cholesterol level~. The alkylated polyethylenimine~ according to the invention have essentially more favorable blle acid-absorbing propertie~ compaxed to colestipol, as is discernable ~rom the experiments described below.
1. In vitro experiment~
1.1 Adsorption batch containing individual ~ile acids Experimental conditions. volume = 10 ml;temparature 37, incubation in a shaking water bath, duration:
hours; medium: isotonic buffered physiological saline solution, pH 7.0; bile acid: 10-15 ~moles;
adsorber (= compound according to the invention or comparison compound): 10-100 mg.
The removal of the~ dsficiencies listed is surprisingly achieved by the use of hiqh molecular weight alkyla~ed polyethylenimines. The non-absorbable macromolecules exhibi~ their action both in soluble form, corre~ponding to the non-crosslinked structure, and in the insoluble state as the crosslinked polymer.
Crosslinked polyethylenimines are described in ~5 Patent 3,332,841. The crosslinking is carried out, inter alia, by means of alkylene groups having 2 to 8 carbon atoms, the molecular weight of the gtarting polymers being between 800 and 100,000. For the txeatment of temporary hyperacidity of the stomach, 0.25 to 5 g are administered per dosage unit. Neither the bincling of bile acid nor lS a lipid-lowering activity of the crosslinked polyethylen-~mines associated with this is described, as without alkylation the polyethylenimines have no binding capacity or only an insignificant binding capacity compared to the gallic acids, depending on the t~e. Owing to the lar~e potential ~harge density, provision can be mada for sufficient binding capacity by means of alkylation and for affinity and binding ~pecificity by means of ~he choice of substituents of appropriate hydrophilic/hydro-phobic character.
The invention therefore relates to non-crosslinked an~
crosslinked alkylated polyethylenimines, wherein ~he starting polyethylenimine has a molecular weight of lO,OOQ to lQ,000,000, the alkylating agent has the formula I
R-X (I) in which X is chlorine~ bromine, iodine, CH3-SO2 O- or ~H3 ~ SO2-O and R is a ~trai~ht-chain or branched Cl-C30-alkyl radical which is optionally substituted by a mono-or bicyclic saturated hyd:rocarbon having 5 to 10 ring carbon atoms, or by a phenyl radical and, in the case of the crosslinked alkylated polyethyl enimines, the crosslinking a~ent is an ~ dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms.
The process for the preparation of the alkylated poly-ethylenimine derivatives accordinq to the invention comprises alkylating a polyethylenimine having a molec-ular weight between 10,000 and 10,000,000 with an alkyl-ating agent of the formula R-X, in which X and R have the meanings indicated, and, if desired, crosslinking with an ~,~-dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms by - me~hods customary in polymer chemistry.
The crosslinking can be carried out before or after the alkylation. Carrying out the crosslinking and the alkyl-ation simultaneously is particularly prefPrred.
Polyethylenimines having a molecular weight above 100,000 are preferably employed.
In the alkylating agents R-X, X is preferably chlorine or bromine.
R is preferably a primary alkyl radical. If the alkyl radicals are substituted by the ring systems mentioned, these are preferably arranged so that they are linked to the polyethylenimine via a spacer having 1 to 4 CH2 yroups. The cyclohexyl radical is particularly suitable as a monocyclic saturated substituent. A suitable bi-cyclic hydrocarbon radical is, for exampleO decalin. A
particularly suitable alkylating a~ent, whose alkyl radical is substituted by phenyl, is benzyl bromide. A
suitable alkylating agent without substituents in the alkyl radical is preferably butyl chloride.
2~8~ ~
The alkylation can be carried out ~n ~everal stage~O In this way, the po~ibility axi~lt~ of fixing different substituent~ to tha same polymer.
The ratio of the alkylating agent employed to the amino groups of the polyethylenimine is 0.2:1 to 5:1, preferab-ly 0.5:1 to 2:1.
By means of the reaction with alkylating agents, a part cf the secondary amino groups in the chain are converted into tertiary and quaternary structures. The foxmation of tertiary amino groups is preferred.
Suitable crosslinking agent~ are, for example, di- and trihaloalkanes, preferably Q,~-dihaloalkanes such as, for - ex~mple, 1,6-dibromohexane and l,10-dibromodecane. The ~mount of the crosslin~er is preferably 2-25 mol-%, relative to the alkylating agent employed.
The alkylated polyethylenimines according to the inven-tion adsorb acids intrinsic to the body, in particul~r gallic acid. In the light of the~3e pxoperties, they are in a position to lower elevated cholesterol level~. The alkylated polyethylenimine~ according to the invention have essentially more favorable blle acid-absorbing propertie~ compaxed to colestipol, as is discernable ~rom the experiments described below.
1. In vitro experiment~
1.1 Adsorption batch containing individual ~ile acids Experimental conditions. volume = 10 ml;temparature 37, incubation in a shaking water bath, duration:
hours; medium: isotonic buffered physiological saline solution, pH 7.0; bile acid: 10-15 ~moles;
adsorber (= compound according to the invention or comparison compound): 10-100 mg.
The bile acid in equilibrium with the adsorbate is determined by means of enzymatic analysis. The methods via 3~-hydroxy- or 7~-hydroxysteroid de-hydrogenases (EC 1.1.1.50 or EC 1.1.1.1~9) were carried out according to the description in Bergmeyer (H.U. Bergmeyer, Methoden der enz~natischen Analyse (Methods of Enzymatic Analysis), 2nd edition 119703, p. 1824) or the product information to product No. H-9506 from SIGMA
CHEMICAL Co. (St. Louis, USA). The proportion of bile acids bound was calculated from the dif-ference between the control batches without adsorber and the complete batches. The experiments for the characterization of the adsorber were carried out with variation of the prestated bil e acid concen-tration or the adsorber amount, and less frequently ~ the incubation period, pH or ionic strength.
An alkylated crosslinked po:Lyalkylenimine according to Example 2 showed a qualitatively better effect owing to stronger cholate binding than colestipol since, incuba~ed with a 2 n~ glycocholate ~olution, 50 mg of colestipol adsorbecl under 6 ~ of the bile acid, Oll the other hand polyimine as in Example 2 absorbed 74 ~ to 76 % of thle bile acid.
1.2 Reversibility testing.
The adsorbate removed from the equilibrium in a batch as described under 1.1 was postincubated with fresh bile acid-free medium and the bile acid released was determined as under 1.1.
In this experiment, it was possible to show that less bile acid was rel~ased again rom adsorbates containing al~ylated crosslinked polyethylenimine as in Example 2 since, from the adsorbate o~ 50 mg of colestipol with 2 mM of glycocholate, 57 % of the gallic acid was released again, on the vther hand _ 7 ~ 8~
only 4 % to 5 % was released from the adsorbate of SO mg of compound according to Example 2.
1.3 Adsorption batch containing bile acid mixtures.
The conditions indicated under 1.1 were modified with respect to blle acid such that 40 ~moles of the tauroconjugate of cholate, chenodeoxycholate, deoxycholate and lithocholate were brought into the batch simultaneously, 20 - 100 mg of the adsorber ~eing used. The i~dividu~l adsorpt~on rate ~
the bile acid was determined by separation and determination by means of high pressure liquid chromatography (N. Parris, Analyt. Bioch~m. 100 (1979) 260~263).
Under these experimental conditions, an alkylated polyethylenimine according to the invention as in Example 1 showed a larger binding rate, as 20 mg of colestipol bound 54 % of a mixture of 4 tauroconju-gated bile acids (each containing 4 mM), on the other hand polyimine as in Example 1 bound 83 ~.
In vivo experiments Young male Wistar rats of a body weight of about 200 g were di~ided into groups of 6 animals and kept on stan-dard feed. In each case samples oE faeces were taken from the animals for analysis before the start of the experi-ment, and 1 and 2 weeks after the start of the experi-ment. If water-soluble, the adsorber was administered daily as a weakly acidic buffered solution at 100, 250 or 500 mg/kg of body weight for 14 days using the stomach tube; as the insoluble substance the adsorber, suspended with 1 ~ of Tylose(R~ (water-soluble cellulose ether) as the vehicle, was incorporated at 250 or 500 mg/kg of body weight daily for 14 ctays using the stomach tube.
In samples of faeces, the neutral steroids were extracted ~8 after homog~nizin~ with chloroform/methanol 2:1 (v/v~, the extract was hydrolyzed and the hydrolyzate was extracted with di~hyl ether/heptane 2:1 (v/v). After evaporating the solvent, the ~ample was sub~ected to gas chromatographic ~eparation and analysi~ (H-CH. Curtius and W. Buryi, Z. Klin. Chemie 4 (1~66) 3B - 42).
The examinations of ~he ~amples of faeces showed the following:
2.1 If the adsorber was a crosslinked alkylated poly-ethylenimine as in Example 2, a more rapid onset of action was determined since, after feeding 250 mg of adsorberJkg of body weight d~ily for 7 days to rats, the additional excretion of unconjugated bile acid in the faece6 was 38 ~ with colestipol, on the other hand it was 115 ~ with the compound as in Example 2.
The effect of polyethyleniminQ i8 obtained with colestipol only after 14 days.
2.2 The desired inhibition of the bacterial conversion of cholesterol in the intestine, associated with an additional excretion of cholesterol, ifi caused to a larger degree by alkylated cro~slinked polyethylen-imine a~ in Example 2, since under identical experi-mental condition~, the cholesterol excretion in rat faeces by cole~tipol i~ increased by 28 %, and by 89 ~ by a compound as in Example 2; at the same time, the coprostanol excretion owing to colestipol changes by ~4 ~, but by -30 ~ owing to a compound as in Example 2.
E`rom the experimental re~ults it can be clearly di~cerned that:
both the non-crosslinked and the cros~linked alkylated polyethylenimines show by means of in vitro adsorption experiments that, compared to colestipol - the quantity of the ~ile acid bound i~ increased by 50-60 ~ (Examples 1 and 2) ~ the binding of cholate is increased 10-~2-fold (Ex~nple 2) - the desorptionrate is lO-:15-fold lower from bile acid polymer~~asorbates (Exampla 2).
In the rat experiment~, it was ~hown that non-cro~6linked polyethylenimines, like crosslinked alkylated polyethyl-enLmines~ given orally in the test range up to soo mg/kg of body weight daily are tolerated without symptoms. It was posaible to show advantages compared to identical dose~ of colestipol, in ~hat O - a more rapid onset of action takes place, whereby the additional bile acid excretion was trlpled after one week' 8 use - the cholesterol elLmination was increased three-fold - the bacterial conversion of cholesterol in the intestine was ~lowed down and in thi~ way th production and excretion of coprostanol was signi-ficantly (= 30 %) reduced (Example 2) The compounds according to the invention are suitable in the light of their properties for use as pharmaceuticals, in particular for lowering increased lipid levels~ The invention therefore al~o relates to the U8Q as hypolipi-demic agent and pharmaceutical agent. In the pharma-ceutical agent~, polyethylenim:ines according to the invention can also be present in the form of phy~iologi-cally tolerated salts with acids.
A particular advantage i~ the use of crosslinked alkyl-ated polyethylenimines7 The crosslinked products can give off no ~ubstances into their environment. This is of significance for the development of a non~toxic mat~rial.
The dose to be administered daily i~ preferably l.0 to lO.0 g, in particular 5 g. It can be divided into several individual dosesP
The compounds according to the invention can be converted as suchg or after addition of customary auxiliaries, into ~8~
forms of preparation for oral administration, such as, for example, tablets, capsules, syrups, aqueous solu-tions, suspensions etc. In this connection, it may be expedient first to bring active compounds obtained in solid form to a desired particle size, for example, by fine grinding. Suitable auxiliaries are, for example, lactose, starch, gelatin, talc etc. The production of tablets is carried out, for example, by means of moist granulation and subsequent compression.
Moreover, the alkylated polyethylenimines can also be incorporated into foodstuffs such as bread, fruit juice etc. or taken together with foodstuffs.
The compounds according to the invention can also be used in combination with other active compounds. Other active - 15 co~pounds which are suitable are, for example, HM~ CoA
~eductase inhibitors, vitamins, geriatric agents and antidiabetic ayents.
The following examples are intended to illustrate the invention:
E~ample 1 44.3 g of polyethylenimine (mol. wt. about 1,000,000) are dissolved in 1.05 1 of H20 in a 4 1 reaction flask;
191.4 g of butyl chloride are aclded and the mixture is heated to reflux for 24 hours with vigorous stirring (500 rpm). A turbid viscous reaction mixture is formed.
1 1 of 2 N NaOH solution is added to this mixture after cooling and the batch is again brought to reflux for 24 hours. After cooling, two phases form. The organic phase is separated off and freed from the solvent in vacuo. The weight of solid is 75.4 g.
The product has a degree of alkylation of about 50 % and, after addition of equivalent amounts of acid, is water-soluble.
E~ample 2 44.3 g (1 mol) of polyethylenimine is dissolved in 1.05 l of H20 in a 4 l reaction flask; 186.6 g of butyl chloride (2 mol) and 48.8 g (0.2 mol) of 1,6-dibromohexane are added and the mixture is heated to reflux for 24 hours with vigorous stirring (500 rpm). A turbid viscous reaction mixture is formed. 1 1 of 2 N NaOH solution is added to this mixture af~er cooling and the batch is brought to reflux again for 24 hours. After cooling the reaction mixture, the solid is filtered off wi-th suction, washed until neutral and dried. The weight is 87.27 ~.
The product is insoluble in water and can be swollen in methanol.
The ratio of starting compound to alkylating agent and crosslinking agent can be varied within certain limits~
Under the reaction conditions indicated, products are then obtained having another degree of alkylation and crosslinking.
~xample 3 The reaction mixture from 4.3 g of polyethylenLmine, 100 ml of water and 29.3 g of 1-chloro-2-cyclohexylethane is heated to reflux for 24 hours, a yellowish turbid mixture being formed. After adding 100 ml of 2 N NaOH
solution, the mixture is heated to reflux ayain for 24 2~ hours. The reaction mixture forms a two-phase system. The organic phase is separated off and freed from the solvent on a rotary evaporator. 15.34 g of a highly viscous material are obtained.
Example 4 A mixture of 88.6 g of polyethylenimine (50 percent in water; = 1 mol), 18606 g of n-bu~yl chloride and 48.8 g of 1,6-dibromohexane in 2 l of water is heated to 80C
for 24 hours under 10 bar of nitrogen in a stirring or shaking autoclave. Th~ protective gas is replaced by 7 bar of ammonia and the mixture is again heated to 80C
for 24 hours.
After cooling the reaction mixture, the precipitate formed is filtered off with suction and washed with water until neutral. The product is washed with methanol and eluted in a column using about 2.5 1 of methanol, about 1.5 1 of 2 N acetic acid, about 2 1 of -2 N ammonia water and finally about 2 1 of methanol. After filtering off with suction, the product is dried in vacuo at a maximum of 50C.
Yield 78 g.
The product can be swollen in various solven~s, but is insoluble.
CHEMICAL Co. (St. Louis, USA). The proportion of bile acids bound was calculated from the dif-ference between the control batches without adsorber and the complete batches. The experiments for the characterization of the adsorber were carried out with variation of the prestated bil e acid concen-tration or the adsorber amount, and less frequently ~ the incubation period, pH or ionic strength.
An alkylated crosslinked po:Lyalkylenimine according to Example 2 showed a qualitatively better effect owing to stronger cholate binding than colestipol since, incuba~ed with a 2 n~ glycocholate ~olution, 50 mg of colestipol adsorbecl under 6 ~ of the bile acid, Oll the other hand polyimine as in Example 2 absorbed 74 ~ to 76 % of thle bile acid.
1.2 Reversibility testing.
The adsorbate removed from the equilibrium in a batch as described under 1.1 was postincubated with fresh bile acid-free medium and the bile acid released was determined as under 1.1.
In this experiment, it was possible to show that less bile acid was rel~ased again rom adsorbates containing al~ylated crosslinked polyethylenimine as in Example 2 since, from the adsorbate o~ 50 mg of colestipol with 2 mM of glycocholate, 57 % of the gallic acid was released again, on the vther hand _ 7 ~ 8~
only 4 % to 5 % was released from the adsorbate of SO mg of compound according to Example 2.
1.3 Adsorption batch containing bile acid mixtures.
The conditions indicated under 1.1 were modified with respect to blle acid such that 40 ~moles of the tauroconjugate of cholate, chenodeoxycholate, deoxycholate and lithocholate were brought into the batch simultaneously, 20 - 100 mg of the adsorber ~eing used. The i~dividu~l adsorpt~on rate ~
the bile acid was determined by separation and determination by means of high pressure liquid chromatography (N. Parris, Analyt. Bioch~m. 100 (1979) 260~263).
Under these experimental conditions, an alkylated polyethylenimine according to the invention as in Example 1 showed a larger binding rate, as 20 mg of colestipol bound 54 % of a mixture of 4 tauroconju-gated bile acids (each containing 4 mM), on the other hand polyimine as in Example 1 bound 83 ~.
In vivo experiments Young male Wistar rats of a body weight of about 200 g were di~ided into groups of 6 animals and kept on stan-dard feed. In each case samples oE faeces were taken from the animals for analysis before the start of the experi-ment, and 1 and 2 weeks after the start of the experi-ment. If water-soluble, the adsorber was administered daily as a weakly acidic buffered solution at 100, 250 or 500 mg/kg of body weight for 14 days using the stomach tube; as the insoluble substance the adsorber, suspended with 1 ~ of Tylose(R~ (water-soluble cellulose ether) as the vehicle, was incorporated at 250 or 500 mg/kg of body weight daily for 14 ctays using the stomach tube.
In samples of faeces, the neutral steroids were extracted ~8 after homog~nizin~ with chloroform/methanol 2:1 (v/v~, the extract was hydrolyzed and the hydrolyzate was extracted with di~hyl ether/heptane 2:1 (v/v). After evaporating the solvent, the ~ample was sub~ected to gas chromatographic ~eparation and analysi~ (H-CH. Curtius and W. Buryi, Z. Klin. Chemie 4 (1~66) 3B - 42).
The examinations of ~he ~amples of faeces showed the following:
2.1 If the adsorber was a crosslinked alkylated poly-ethylenimine as in Example 2, a more rapid onset of action was determined since, after feeding 250 mg of adsorberJkg of body weight d~ily for 7 days to rats, the additional excretion of unconjugated bile acid in the faece6 was 38 ~ with colestipol, on the other hand it was 115 ~ with the compound as in Example 2.
The effect of polyethyleniminQ i8 obtained with colestipol only after 14 days.
2.2 The desired inhibition of the bacterial conversion of cholesterol in the intestine, associated with an additional excretion of cholesterol, ifi caused to a larger degree by alkylated cro~slinked polyethylen-imine a~ in Example 2, since under identical experi-mental condition~, the cholesterol excretion in rat faeces by cole~tipol i~ increased by 28 %, and by 89 ~ by a compound as in Example 2; at the same time, the coprostanol excretion owing to colestipol changes by ~4 ~, but by -30 ~ owing to a compound as in Example 2.
E`rom the experimental re~ults it can be clearly di~cerned that:
both the non-crosslinked and the cros~linked alkylated polyethylenimines show by means of in vitro adsorption experiments that, compared to colestipol - the quantity of the ~ile acid bound i~ increased by 50-60 ~ (Examples 1 and 2) ~ the binding of cholate is increased 10-~2-fold (Ex~nple 2) - the desorptionrate is lO-:15-fold lower from bile acid polymer~~asorbates (Exampla 2).
In the rat experiment~, it was ~hown that non-cro~6linked polyethylenimines, like crosslinked alkylated polyethyl-enLmines~ given orally in the test range up to soo mg/kg of body weight daily are tolerated without symptoms. It was posaible to show advantages compared to identical dose~ of colestipol, in ~hat O - a more rapid onset of action takes place, whereby the additional bile acid excretion was trlpled after one week' 8 use - the cholesterol elLmination was increased three-fold - the bacterial conversion of cholesterol in the intestine was ~lowed down and in thi~ way th production and excretion of coprostanol was signi-ficantly (= 30 %) reduced (Example 2) The compounds according to the invention are suitable in the light of their properties for use as pharmaceuticals, in particular for lowering increased lipid levels~ The invention therefore al~o relates to the U8Q as hypolipi-demic agent and pharmaceutical agent. In the pharma-ceutical agent~, polyethylenim:ines according to the invention can also be present in the form of phy~iologi-cally tolerated salts with acids.
A particular advantage i~ the use of crosslinked alkyl-ated polyethylenimines7 The crosslinked products can give off no ~ubstances into their environment. This is of significance for the development of a non~toxic mat~rial.
The dose to be administered daily i~ preferably l.0 to lO.0 g, in particular 5 g. It can be divided into several individual dosesP
The compounds according to the invention can be converted as suchg or after addition of customary auxiliaries, into ~8~
forms of preparation for oral administration, such as, for example, tablets, capsules, syrups, aqueous solu-tions, suspensions etc. In this connection, it may be expedient first to bring active compounds obtained in solid form to a desired particle size, for example, by fine grinding. Suitable auxiliaries are, for example, lactose, starch, gelatin, talc etc. The production of tablets is carried out, for example, by means of moist granulation and subsequent compression.
Moreover, the alkylated polyethylenimines can also be incorporated into foodstuffs such as bread, fruit juice etc. or taken together with foodstuffs.
The compounds according to the invention can also be used in combination with other active compounds. Other active - 15 co~pounds which are suitable are, for example, HM~ CoA
~eductase inhibitors, vitamins, geriatric agents and antidiabetic ayents.
The following examples are intended to illustrate the invention:
E~ample 1 44.3 g of polyethylenimine (mol. wt. about 1,000,000) are dissolved in 1.05 1 of H20 in a 4 1 reaction flask;
191.4 g of butyl chloride are aclded and the mixture is heated to reflux for 24 hours with vigorous stirring (500 rpm). A turbid viscous reaction mixture is formed.
1 1 of 2 N NaOH solution is added to this mixture after cooling and the batch is again brought to reflux for 24 hours. After cooling, two phases form. The organic phase is separated off and freed from the solvent in vacuo. The weight of solid is 75.4 g.
The product has a degree of alkylation of about 50 % and, after addition of equivalent amounts of acid, is water-soluble.
E~ample 2 44.3 g (1 mol) of polyethylenimine is dissolved in 1.05 l of H20 in a 4 l reaction flask; 186.6 g of butyl chloride (2 mol) and 48.8 g (0.2 mol) of 1,6-dibromohexane are added and the mixture is heated to reflux for 24 hours with vigorous stirring (500 rpm). A turbid viscous reaction mixture is formed. 1 1 of 2 N NaOH solution is added to this mixture af~er cooling and the batch is brought to reflux again for 24 hours. After cooling the reaction mixture, the solid is filtered off wi-th suction, washed until neutral and dried. The weight is 87.27 ~.
The product is insoluble in water and can be swollen in methanol.
The ratio of starting compound to alkylating agent and crosslinking agent can be varied within certain limits~
Under the reaction conditions indicated, products are then obtained having another degree of alkylation and crosslinking.
~xample 3 The reaction mixture from 4.3 g of polyethylenLmine, 100 ml of water and 29.3 g of 1-chloro-2-cyclohexylethane is heated to reflux for 24 hours, a yellowish turbid mixture being formed. After adding 100 ml of 2 N NaOH
solution, the mixture is heated to reflux ayain for 24 2~ hours. The reaction mixture forms a two-phase system. The organic phase is separated off and freed from the solvent on a rotary evaporator. 15.34 g of a highly viscous material are obtained.
Example 4 A mixture of 88.6 g of polyethylenimine (50 percent in water; = 1 mol), 18606 g of n-bu~yl chloride and 48.8 g of 1,6-dibromohexane in 2 l of water is heated to 80C
for 24 hours under 10 bar of nitrogen in a stirring or shaking autoclave. Th~ protective gas is replaced by 7 bar of ammonia and the mixture is again heated to 80C
for 24 hours.
After cooling the reaction mixture, the precipitate formed is filtered off with suction and washed with water until neutral. The product is washed with methanol and eluted in a column using about 2.5 1 of methanol, about 1.5 1 of 2 N acetic acid, about 2 1 of -2 N ammonia water and finally about 2 1 of methanol. After filtering off with suction, the product is dried in vacuo at a maximum of 50C.
Yield 78 g.
The product can be swollen in various solven~s, but is insoluble.
Claims (8)
1. A non crosslinked or crosslinked alkylated polyethyl-enimine, wherein the starting polyethylenimine has a molecular weight of 10,000 to 10,000,000, the alkylating agent has the formula I
R-X (I) in which X is chlorine, bromine, iodine, CH3-SO2-O- or and R is a straight-chain or branched C1-C30-alkyl radical which is optionally substituted by a mono-or bicyclic saturated hydrocarbon having 5 to 10 ring carbon atoms, or by a phenyl radical and, in the case of the crosslinked alkylated polyethyl-enimines, the crosslinking agent is an .alpha.,.omega.-dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms.
R-X (I) in which X is chlorine, bromine, iodine, CH3-SO2-O- or and R is a straight-chain or branched C1-C30-alkyl radical which is optionally substituted by a mono-or bicyclic saturated hydrocarbon having 5 to 10 ring carbon atoms, or by a phenyl radical and, in the case of the crosslinked alkylated polyethyl-enimines, the crosslinking agent is an .alpha.,.omega.-dihaloalkane having 2-10 carbon atoms or a higher functionalized haloalkane having 2-10 carbon atoms.
2. A process for the preparation of non-crosslinked or crosslinked alkylated polyethylenimine derivatives, which comprises alkylating a polyethylenimine having a molec-ular weight between 10,000 and 10,000,000 with an alkyl-ating agent of the formula R-X, in which X and R have the meanings indicated and, if desired, crosslinking with an dihaloalkane having 2-10 carbon atoms or higher functionalized haloalkane having 2-10 carbon atoms by methods customary in polymer chemistry.
3. The process as claimed in claim 2, wherein one or more of the following measures are observed:
a) polyethylenimine having a molecular weight above 100,000 are employed, b) in the alkylating agents R-X, X is chlorine or bromine, c) in the alkylating agents, R is a primary alkyl radical which is optionally substituted by a cyclo-hexyl, decalin or phenyl radical, where these substituents are arranged such that they are linked to the polyethylenimine via a spacer having 1 to 4 CH2 groups, d) the ratio of the alkylating agent employed to the amino groups of the polyethylenimine is 0. 5 t 1 to 2:1, e) the crosslinking agent is 1,6-dibromohexane or 1,10-dibromodecane, f) alkylation and crosslinking are carried out simultaneously.
a) polyethylenimine having a molecular weight above 100,000 are employed, b) in the alkylating agents R-X, X is chlorine or bromine, c) in the alkylating agents, R is a primary alkyl radical which is optionally substituted by a cyclo-hexyl, decalin or phenyl radical, where these substituents are arranged such that they are linked to the polyethylenimine via a spacer having 1 to 4 CH2 groups, d) the ratio of the alkylating agent employed to the amino groups of the polyethylenimine is 0. 5 t 1 to 2:1, e) the crosslinking agent is 1,6-dibromohexane or 1,10-dibromodecane, f) alkylation and crosslinking are carried out simultaneously.
4. A pharmaceutical preparation which contains a compound as claimed in claim 1 or its physiologically tolerated salt with an acid.
5. A method for the production of a pharmaceutical preparation, which comprises converting a compound as claimed in claim 1 into a suitable form for administration.
6. The use of a compound as claimed in claim 1 as a hypolipidemic agent.
7. The use of compounds as claimed in claim 1 as an additive in foodstuffs and fruit juices.
8. The non-crosslinked or crosslinked alkylated polyethylenimine as claimed in claim 1, and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3901527A DE3901527A1 (en) | 1989-01-20 | 1989-01-20 | ALKYLATED POLYETHYLENE IMIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND PHARMACEUTICAL PREPARATIONS |
| DEP3901527.0 | 1989-01-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2008114A1 true CA2008114A1 (en) | 1990-07-20 |
Family
ID=6372414
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002008114A Abandoned CA2008114A1 (en) | 1989-01-20 | 1990-01-19 | Alkylated polyethylenimine derivatives, process for their preparation, their use as pharmaceuticals and pharmaceutical preparation |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0379161B1 (en) |
| JP (1) | JPH02232229A (en) |
| AT (1) | ATE111931T1 (en) |
| AU (1) | AU624215B2 (en) |
| CA (1) | CA2008114A1 (en) |
| DE (2) | DE3901527A1 (en) |
| DK (1) | DK0379161T3 (en) |
| ES (1) | ES2063173T3 (en) |
| FI (1) | FI900297A0 (en) |
| IE (1) | IE65618B1 (en) |
| IL (1) | IL93098A0 (en) |
| NO (1) | NO900279L (en) |
| NZ (1) | NZ232149A (en) |
| PT (1) | PT92880B (en) |
| ZA (1) | ZA90394B (en) |
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| EP0534316A1 (en) * | 1991-09-21 | 1993-03-31 | Hoechst Aktiengesellschaft | Use of alkylated polyethylenimines to concentrate bile acids |
| EP0534304A1 (en) * | 1991-09-21 | 1993-03-31 | Hoechst Aktiengesellschaft | Cycloalkylated polyethylenimines and their use as hypolipemic agents |
| KR0179675B1 (en) * | 1992-01-14 | 1999-03-20 | 나까토미 히로타카 | Cholesterol level depressant |
| ES2080549T3 (en) * | 1992-03-28 | 1996-02-01 | Hoechst Ag | MEDICINES BASED ON POLYHYDROXYMETHYLENE DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND USE. |
| DK0580078T3 (en) * | 1992-07-22 | 1998-05-25 | Hoechst Ag | Polyvinylamine derivatives with hydrophilic centers, process for their preparation as well as the use of the compounds as drugs, carriers of active substances and food aid. |
| ATE146193T1 (en) * | 1992-07-22 | 1996-12-15 | Hoechst Ag | CROSS-LINKED, NITROGEN-CONTAINING VINYL COPOLYMERS, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THESE COMPOUNDS |
| US5667775A (en) | 1993-08-11 | 1997-09-16 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
| US5496545A (en) * | 1993-08-11 | 1996-03-05 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
| TW474813B (en) | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
| US6268392B1 (en) | 1994-09-13 | 2001-07-31 | G. D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors |
| US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
| US6107494A (en) * | 1994-09-13 | 2000-08-22 | G.D. Searle And Company | Substituted 5-aryl-benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
| US5994391A (en) * | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
| US6262277B1 (en) | 1994-09-13 | 2001-07-17 | G.D. Searle And Company | Intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
| ATE228012T1 (en) | 1998-12-23 | 2002-12-15 | Searle Llc | COMBINATIONS OF ILEUMGALLIC ACID TRANSPORT INHIBITORS AND BALE ACID SEQUESTRING AGENTS FOR CARDIOVASCULAR INDICATIONS |
| WO2000038726A1 (en) | 1998-12-23 | 2000-07-06 | G.D. Searle Llc | Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications |
| WO2000038722A1 (en) | 1998-12-23 | 2000-07-06 | G.D. Searle & Co. | COMBINATIONS OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS AND HMG CoA REDUCTASE INHIBITORS FOR CARDIOVASCULAR INDICATIONS |
| EA200100707A1 (en) | 1998-12-23 | 2001-12-24 | Джи.Ди.Сирл Ллс | COMBINATIONS OF INHIBITORS OF TRANSPORT OF BILK ACIDS IN THE SUBJECTIVE AND FIBRIN ACID DERIVATIVES FOR THE CARDIOVASCULAR INDICATIONS |
| WO2000038724A1 (en) | 1998-12-23 | 2000-07-06 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications |
| AU3103800A (en) | 1998-12-23 | 2000-07-31 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acidderivatives for cardiovascular indications |
| US6569905B1 (en) | 1998-12-23 | 2003-05-27 | G.D. Searle, Llc | Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications |
| US6733780B1 (en) | 1999-10-19 | 2004-05-11 | Genzyme Corporation | Direct compression polymer tablet core |
| WO2001068637A2 (en) | 2000-03-10 | 2001-09-20 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
| DE10065710A1 (en) * | 2000-12-29 | 2002-07-04 | Bayer Ag | Medicament containing a polyamine as an active substance |
| MXPA04003524A (en) | 2001-11-02 | 2004-07-23 | Searle Llc | Novel mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (asbt) and taurocholate uptake. |
| AU2003207431A1 (en) | 2002-01-17 | 2003-09-02 | Pharmacia Corporation | Novel alkyl/aryl hydroxy or keto thiepines. |
| GB0221942D0 (en) * | 2002-09-20 | 2002-10-30 | Univ Strathclyde | Drug delivery |
| US7985418B2 (en) | 2004-11-01 | 2011-07-26 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| WO2007027566A2 (en) | 2005-09-02 | 2007-03-08 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
| KR101574072B1 (en) | 2005-09-15 | 2015-12-04 | 젠자임 코포레이션 | Sachet formulation for amine polyemrs |
| MA41202A (en) | 2014-12-18 | 2017-10-24 | Genzyme Corp | CROSS-LINKED POLYDIALLYMINE COPOLYMERS FOR THE TREATMENT OF TYPE 2 DIABETES |
| CN110907543A (en) * | 2019-09-29 | 2020-03-24 | 重庆健能医药开发有限公司 | Experimental method for adsorbing bile acid of hydrotalcite chewable tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3251778A (en) * | 1960-08-04 | 1966-05-17 | Petrolite Corp | Process of preventing scale |
| US3332841A (en) * | 1961-10-04 | 1967-07-25 | Lilly Co Eli | Method of treating hyperacidity |
| JPS5548221A (en) * | 1978-10-04 | 1980-04-05 | Nippon Oil Co Ltd | Preparation of polyhexamethyleneimine |
| JPS5566513A (en) * | 1978-11-14 | 1980-05-20 | Ono Pharmaceut Co Ltd | Drug for arteriosclerosis comprising high polymer compound as active constituent |
| JPS62243620A (en) * | 1986-04-17 | 1987-10-24 | Asahi Chem Ind Co Ltd | Surface-modified wholly aromatic polyamide formed article and production thereof |
-
1989
- 1989-01-20 DE DE3901527A patent/DE3901527A1/en not_active Withdrawn
-
1990
- 1990-01-17 EP EP90100887A patent/EP0379161B1/en not_active Expired - Lifetime
- 1990-01-17 ES ES90100887T patent/ES2063173T3/en not_active Expired - Lifetime
- 1990-01-17 AT AT90100887T patent/ATE111931T1/en not_active IP Right Cessation
- 1990-01-17 PT PT92880A patent/PT92880B/en not_active IP Right Cessation
- 1990-01-17 DK DK90100887.0T patent/DK0379161T3/en active
- 1990-01-17 DE DE59007178T patent/DE59007178D1/en not_active Expired - Fee Related
- 1990-01-18 FI FI900297A patent/FI900297A0/en not_active Application Discontinuation
- 1990-01-18 IL IL93098A patent/IL93098A0/en not_active IP Right Cessation
- 1990-01-18 NZ NZ232149A patent/NZ232149A/en unknown
- 1990-01-19 IE IE21490A patent/IE65618B1/en not_active IP Right Cessation
- 1990-01-19 ZA ZA90394A patent/ZA90394B/en unknown
- 1990-01-19 AU AU48618/90A patent/AU624215B2/en not_active Ceased
- 1990-01-19 CA CA002008114A patent/CA2008114A1/en not_active Abandoned
- 1990-01-19 NO NO90900279A patent/NO900279L/en unknown
- 1990-01-19 JP JP2008569A patent/JPH02232229A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8263223B2 (en) | 1999-06-01 | 2012-09-11 | Biointeractions, Ltd. | Coated surfaces for immobilizing negatively charged anticoagulating agents from blood fluid |
| US8343084B2 (en) | 1999-06-01 | 2013-01-01 | Closys Corporation | Clotting cascade initiating apparatus and methods of use and methods of closing wounds |
| US10973503B2 (en) | 2010-06-24 | 2021-04-13 | St. Croix Surgical Systems, Llc | Failsafe percutaneous wound barrier |
Also Published As
| Publication number | Publication date |
|---|---|
| PT92880A (en) | 1990-07-31 |
| NO900279L (en) | 1990-07-23 |
| IE900214L (en) | 1990-07-20 |
| DK0379161T3 (en) | 1995-01-16 |
| AU624215B2 (en) | 1992-06-04 |
| NO900279D0 (en) | 1990-01-19 |
| EP0379161A2 (en) | 1990-07-25 |
| EP0379161B1 (en) | 1994-09-21 |
| IL93098A0 (en) | 1990-11-05 |
| ZA90394B (en) | 1991-04-24 |
| DE3901527A1 (en) | 1990-07-26 |
| JPH02232229A (en) | 1990-09-14 |
| DE59007178D1 (en) | 1994-10-27 |
| ES2063173T3 (en) | 1995-01-01 |
| AU4861890A (en) | 1990-07-26 |
| IE65618B1 (en) | 1995-11-01 |
| PT92880B (en) | 1995-12-29 |
| NZ232149A (en) | 1991-12-23 |
| EP0379161A3 (en) | 1991-07-31 |
| FI900297A0 (en) | 1990-01-18 |
| ATE111931T1 (en) | 1994-10-15 |
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| FZDE | Discontinued |