GB2036048A - Polymer compounds, process for their preparation and arteriosclerosis treating agents containing them - Google Patents
Polymer compounds, process for their preparation and arteriosclerosis treating agents containing them Download PDFInfo
- Publication number
- GB2036048A GB2036048A GB7939305A GB7939305A GB2036048A GB 2036048 A GB2036048 A GB 2036048A GB 7939305 A GB7939305 A GB 7939305A GB 7939305 A GB7939305 A GB 7939305A GB 2036048 A GB2036048 A GB 2036048A
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- Prior art keywords
- compound
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- nitrogen
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- polyethylenepolyamine
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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
- C08G73/022—Preparatory process from polyamines and epihalohydrins
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Abstract
A crosslinked polymer is obtained from ammonia, ethylenediamine or a polyethylenepolyamine having a degree of repeating unit of 2-1500, and a bifunctional compound of the formula: Y-M-Z wherein Y is a -CH2X group (wherein X represents a chlorine, bromine or iodine atom) or a <IMAGE> group, M is a single bond, a -(CH2)m- group (wherein M represents 1, 2 or 3), a -CH2-O-CH2-group or a -CH2-O-(CH2)k-O-CH2 group (wherein k represents 1,2,3 or 4), and Z is a -CH(OH)-CH2X group (wherein X is the same as hereinbefore defined) or a <IMAGE> group, and 20 percent or more of the nitrogen atoms thereof are combined with lower alkyl groups to form a quaternary ammonium salt. An arteriosclerosis treating agent containing the compound as an active ingredient and a process for preparing the compound are also disclosed.
Description
SPECIFICATION
Polymer compounds, process for their preparation and arteriosclerosis treating agents containing them
The present invention relates to polymer compounds, process for their preparation and arteriosclerosis treating agents containing them.
Cholesterol absorption-inhibiting drugs have been proposed for treating lipidemia which is closely related to arteriosclerosis. Cholesterol is a precursor of steroid hormones such as adrenocortical hormone and sex hormone and is known to exhibit various important physiological effects. On the other hand, it has been pointed out that an abnormal increase of the cholesterol concentration in blood leads to various circulatory disorders such as arteriosclerosis. Among the cholesterol absorption inhibiting drugs, there is a class of drugs which are believed to reduce the cholesterol value in blood by absorbing bile acids which are believed to be the metabolites of cholesterol in the digestive organs. As examples of these materials, there are known a cross-linked polymer of styrene and divinylbenzene and a crosslinked polymer of polyethylenepolyamine and epichlorohydrin, as the units.However, there is still scope for improvement in terms of their effect as cholesterol absorption inhibiting drugs and/or their side effects.
In one aspect of the present invention, there is provided a compound which is a crosslinked
polymer obtained from a nitrogen-containing compound selected from ammonia, ethylenediamine and a polyethylenepolyamine having a degree of repeating units of 2-1 500, and a bifunctional compound of the formula:: Y-M-Z wherein Y represents a -CH2X group (wherein X represents a chlorine, bromine or iodine atom) or a
group, M represents a single bond, a -(CH2)rn-group (wherein m represents 1, 2 or 3), a -CH2-0-CH2-group or-CH2-O-(CH2)k-O CH2-group (wherein k represents 1, 2, 3 or 4), and Z represents a -CH(OH)-CH2X group (wherein X is as hereinbefore defined) or
group, 20 percent or more of the nitrogen atoms of which are combined with lower alkyl groups to form a quaternary ammonium salt, or a pharmaceutically acceptable non-toxic salt thereof.
In another aspect, the present invention provides an arteriosclerosis treating agent comprising, as an active ingredient, a compound as defined in the last preceding paragraph, and a pharmaceutically acceptable carrier.
In a further aspect, the present invention provides a process for preparing a crosslinked copolymer compound which comprises reacting a nitrogen-containing compound selected from ammonia, ethylenediamine and a polyethylenepolyamine having a degree of repeating units of 2-1 500, and a bifunctional compound of the formula:: Y-M-Z wherein Y represents a -CH2X group (wherein X represents a chlorine, bromine or iodine atom) or a
group, M represents a single bond, a -(CH2)rn-group (wherein m represents 1, 2 or 3), a -CH2-0-CH2 group or a CH20(CH2)-O-CH2-grnup (wherein k represents 1, 2, 3 or 4) and
Z represents a -CH(OH)-CH2X group (wherein X is the same as hereinbefore defined) or a
group, and 20 percent or more of the nitrogen atoms of which being alkylated with an alkylating agent to form a quaternary ammonium salt.
An object of the present invention is to provide arteriosclerosis treating agents which reduce blood lipids related to arteriosclerosis but do not exhibit substantial side effects, and this object has now been attained by utilizing, as the active ingredient, a polymer compound which is a crosslinked polymer obtained from a nitrogen-containing compound selected from the group consisting of ammonia, ethylenediamine and a polyethylenepolyamine having a degree of repeating units of 2-1 500 and a bifunctional compound such asepihalohydrin, 20 percent or more of the nitrogen atoms of which are combined with lower alkyl groups to form a quaternary ammonium salt, or a pharmaceutically acceptable, non-toxic salt thereof.The polymer compound or its pharmaceutically acceptable, non-toxic salt is remarkably excellent as the cholesterol absorption inhibiting drug and does not exhibit substantially side effects.
Examples of the bifunctional compound having the formula: Y-M-Z wherein the various symbols are as hereinbefore defined, are epichiorhydrin, glycerol-1,3- dichlorohydrin, 1,2 :3,4-bisepolybutane, bisepoxypropyl ether, 1,4-butanediol bisepoxypropyl ether.
Preferably the bifunctional compound is a compound of the formula:
wherein X is the same as hereinbefore defined.
Preferably the nitrogen-containing compound is ammonia, ethylenediamine or a straight chain or
branched chain polyethylenepolyamine having a degree of repeating units of 2-1200, and more
preferably is a polyethylenepolyamine having a degree of repeating units of 2-10 and an average
molecular weight of 103---477 and a polyethylenepolyamine having a degree of repeating unit of 930--1 1 63 and an average molecular weight of about 40,000-about 50,000.
The crosslinked polymer of the bifunctional compound and the nitrogen-containing compound can
be obtained by reacting the nitrogen-containing compound and the bifunctional compound in a
conventional organic solvent, in an aqueous solvent or in water. In this case, it is preferred to react the
nitrogen-containing compound and the bifunctional compound in such ratio that the bifunctional
compound per nitrogen atom of the nitrogen-containing compound is
1 1
10 n+1 or more of molecule, wherein n represents the degree of repeating unit of the polyethylenepolyamine of the nitrogen containing compound or n=O for ammonia or n=1 for ethylenediamine.Further, when the nitrogen atoms of the cross-linked polymer are combined with lower alkyl groups to form a quaternary ammonium salt, it may be effected by reacting once or more with an alkylating agent having a lower alkyl group in an organic solvent or aqueous solvent inert to the alkylating agent. The alkylating agent having the lower alkyl group referred to herein means a compound having the formula: RX wherein R represents a straight chain or branched alkyl of 1-5 carbon atoms and X represents a chlorine, bromine or iodine atom or the formula: R2SO4 wherein R is as defined above While the alkylating agent can be used alone or in mixture, where they are employed for more than one reactions, it is preferred to use a more sterically hindered alkylating agent first.Examples of the alkylating agent are methyl iodide, methyl bromide, methyl chloride, ethyl iodide, dimethylsulfuric acid, diethylsulfuric acid.
In the present invention, 35 percent or more of the nitrogen atoms of said crosslinked polymer are preferably quaternarized although 20 percent or more is adequate.
The pharmaceutically acceptable, non-toxic salt of the polymer compound of the present invention means a residue of an inorganic acid such as hydrochloric acid, phosphoric acid, or a residue of an organic acid such as acetic acid or oxalic acid. In order to produce said salt, it is possible to utilize the acid residue of the alkylating agent. Alternatively, said salt can be obtained by washing the produced polymer with an aqueous alkali hydroxide (e.g. sodium hydroxide) solution, washing with deionized water and subsequently washing with an aqueous solution of an acid or a salt having the desired acid residue.
The polymer compound or its pharmaceutically acceptable, non-toxic salt of the present invention
may be used in any form combined with any carrier which can be administered orally. Examples of such
carrier are solid or liquid medical base materials as well as beverages and food. Representative
examples of the solid medical base material are lactose, sugar, starch, dextrin, glucose, mannitol,
calcium carbonate, kaolin, calcium phosphate.
Examples of the dosage form are powders, granules, tablets, coated tablets, capsules, pills.
The hydrochloric acid salt of the polymer compound of the present invention was tested for its
acute toxicity. In a test using rats, with the dosages of 1 g/kg-body weight for the oral administration
and 4 g/kg-body weight for the intraperitoneal administration, there was no death case observed, and therefore the LD50 value was not obtained. Further, when rats were administered with the dosage of 4 g/kg-body weight incorporated in their daily feed for 1 4 consecutive days, no toxicity was observed. The dosage of the polymer compound or its pharmaceutically acceptable, non-toxic salt of the present invention when administered to a patient who needs the treatment is 1-100 g daily and preferably 1-20 g daily.
The mode of administration is the oral administration and the above dosage is given in three to four doses a day.
The present invention will be explained in the following examples, reference examples and the results of the tests on the effects of the compounds of the present invention as arteriosclerosis treating agents.
REFERENCE EXAMPLE 1
A mixed solution of 760 g of tetraethylenepentamine, 8 1 of deionized water and 390 ml of epichiorohydrin was stirred at 25 OC for an hour and reacted at 900C for an hour. After cooled to 30 C, it was added with 300 ml of 50% aqueous sodium hydroxide solution and then with 390 ml of epichlorohydrin, and was reacted at 250C for an hour and then at 900C for five hours. The reaction mixture was adjusted to pH 6 and ethanol was added to precipitate the polymer. The rubbery reaction mixture was washed with ethanol, dried and ground on a grinder to obtain a finely-divided crosslinked polymer, which was provided as Sample d.
Physical properties of Sample d
Degree of swelling: 5.63 ml/g (dry resin)
Weak base exchange capacity: 3.89 meg/g (dry resin)
REFERENCE EXAMPLE 2
For comparison, a commercially available cholesterol absorption inhibiting agent, "Questran" (registered trademark, manufactured by Mead Johnson Co.) was used. The components other than the resin were removed by washing to purify the polymer. The polymer was further treated to the chloride type, which was provided as Sample c.
Physical properties of Sample c
Degree of swelling: 6.0 ml/g (dry resin)
Strong base exchange capacity: 4.2 meg/g (dry resin)
EXAMPLE 1
One liter of 11% aqueous sodium hydroxide solution was added to 200 g of Sample d obtained in
Reference Example 1 and stirred at room temperature for 8 hours. The polymer was then washed with water, strained and reacted with 355 g of methyl iodide and 1.5 1 of methanol for 5 hours. Thereafter, 500 ml of 20% aqueous sodium hydroxide solution and 50 g of methyl iodide were added to the reaction mixture and stirred at room temperature for 2 hours and the stirring was continued for another 6 hours with heating. The reaction mixture was filtered, washed with water, added with one liter of 11% aqueous sodium hydroxide solution, stirred at room temperature for 8 hours and washed with dionized water.The resin was strained and reacted with 3-50 g of methyl iodide and 1.5 1 of methanol at 500C for 5 hours. After the reaction, the reaction mixture was filtered, washed with water, treated with 2 N hydrochloric acid, added with 3 1 of water and heated at-900C for 6 hours.
Then, the polymer was washed again with 5 1 of 2 N sodium hydroxide, 10 1 of dionized water, 5 1 of 2N saline and 10 1 of deionized water successively and strained to obtain the desired hydrochloride salt of the polymer compound, which was provided as Sample a.
Physical properties of Sample a
Degree of swelling: 16.6 ml/g (dry resin)
Weak base exchange capacity: 5.79 meq/g (dry resin)
Strong base exchange capacity: 4.54 meq/g (dry resin)
EXAMPLE 2
Seven and four-tenth kg of a 30% aqueous solution of polyethyleneimine were dispersed in 1 5.8 kg of chlorobenzene to which 0.8 kg of epichlorohydrin was added dropwise at 20--300C. They are reacted at 50 C for 3 hours and then at 1 300C for 5 hours. After the reaction, the polymer and chlorobenzene were separated by filtration and the polymer was purified to remove the contained chlorobenzene and then dried. Nine hundred and sixty grams of the obtained crosslinked polymer were suspended in 4.3 1 of methanol to which 870 g of methyl iodide were added dropwise and the mixture was reacted at 500C for 5 hours.After the reaction, the reaction mixture was filtered andthe polymer was washed with 10 1 of 2 N sodium hydroxide and then with 10 1 of deionized water. Further, the polymer was suspended in 4.3 1 of methanol, 870 g of methyl iodide were added dropwise and they were reacted at 500C for 5 hours. After the reaction, the mixture was filtered and the polymer was washed with 10 1 of 2 N sodium hydroxide and then with 10 1 of deionized water. The obtained resin was again suspended in 4.3 1 of methanol, to which 870 g of methyl iodide were added dropwise and the mixture was reacted at 500C for 5 hours.After the reaction, the mixture was filtered, 5 1 of deionized water were added and heated at 95 0C for 8 hours after which the resin was washed with 5 1 of methanol, 10 1 of deionized water, 10 1 of 2 N sodium hydroxide, 10 1 of deionized water, 20 1 of 5 JO saline and 50 1 of deionized water successively. The thus obtained resin was then dried to obtain 1 kg of the desired hydrochloride of the polymer, which was provided as Sample b.
Physical properties of Sample b
Degree of swelling: 9.83 ml/g (dry resin)
Weak base exchange capacity: 2.00 meq/g (dry resin)
Strong base exchange capacity: 4.62 meq/g (dry resin)
EXAMPLES 3 AND 4
Five hundred gelatin capsules for the oral administration were prepared from the following formulation, each capsule containing 500 mg of dry sample of Example 1 or 2.
Sample a of Example 1 or Sample b of Example 2 250 g
J.P. VIII talc 25 g
J.P. Vlil magnesium stearate 1g The above composition was thoroughly mixed and filled into hard capsules of an appropriate size.
The capsules are orally administered in the dosage of 2-3 capsules 3 91 times a day.
TEST EXAMPLE 1
The degree of adsorption of cholic acid of Samples a and b of the Examples 1 and 2, respectively, were compared with those of Samples d and c of Reference Examples 1 and 2, respectively, by in vitro test described as follows.
Each sample was ground in a mortar, dried at 1 000C under reduced pressure for 7 hours and an aliquot of a specified amount was taken. The aliquot was buffered with phosphate buffer, stirred at 350C for 30 minutes and adjusted to the predetermined pH. A specific amount of a separately prepared, phosphate-buffered sodium cholate-solution having a concentration of 50 M was added to each sample suspension adjusted to the predetermined pH. After reacting at 350C for an hour, each sample was centrifugally separated and a specified amount of each supernatant liquid was taken and the amount of cholic acid remaining therein was measured to determine the amount of cholic acid adsorbed on the sample.Tests were carried out with different sample weights varying from 20-100 mg for each sample to obtain the amount of cholic acid adsorbed at each sample weight. The weight of the sample and the exchange capacity at 50% adsorption of sodium cholate were obtained from the graph. The results are summarized in Table 1.
TABLE 1
At 50% Adsorption of At 50% Adsorption of Sodium Sodium Cholate at pH 7.00 Oholsate at pH 7.50
Total Sample Total Sample
Sample Wt. Ex. Capacity Sample Wt. Ex. Capacity
Sample (mg) (meq) (mg) (meq)
a 89.6 0.926 122.6 1.267
b 93.2 0.617 132.2 0.875
c 132.9 0.517 171.5 0.667
d 137.7 1.650 193.8 2.392
TEST EXAMPLE 2
Samples a and b of Examples 1 and 2, respectively, were tested for their effects of reducing blood lipids which were closely related to arteriosclerosis, by an animal test using rats.
Five-week-old JCL-Wistar strain, male rats (body weight about 110 g) were divided into two groups. One group was fed with a commercially available solid feed (Oriental Solid Feed manufactured by NMF-Oriental Yeast Co.). The other group was fed with a cholesterol rich feed for two weeks to produce rats suffering from cholesterolemia. The thus obtained rats with cholesterolemia were divided into Control group and Test groups to which each sample was administered. The rats of the Control group were fed with a cholesterol rich feed and each Test group was fed with a cholesterol rich feed containing 1% of each sample for two weeks. The feed was given at 1 0 g/1 00 g-body weight per day.
The body weight, serum cholesterol, serum triglyceride, serum ,B-lipoprotein, liver weight, liver cholesterol and total liver lipids before and after feeding were measured on each of the Normal group (fed with normal feed), Control group and Test groups. The results are given in Tabies 2 and 3. TABLE 2
Body Weight (g) Serum Cholesterol
(mg/dl)
No. Before After
of admin. admin.Before After Serum Triglyceride
Feed rats (on 2 wks.) (on 4 wks.) admin. admin. (mg/dl)
Normal Normal feed 10 Ave. 177.9 288.4 63.7 87.2 65.4 group (10 g/100 g Err. #2.2 #3.7 #3.7 #1.7 #4.9
by wt.)
Control Cholesterol 10 Ave. 183.0 269.5 525.0 323.4 115.7 group rich feed Err. #2.1 #2.7 #36.6 #29.5 #19.2
(10 g/100 g
by wt.)
Test Cholesterol 10 Ave. 184.2 270.8 537.8 140.0* 93.8 group rich feed Err. #2.6 #3.6 #28.8 #14.6 #17.5 with +
Sample a Sample a
Test Cholesterol 10 Ave. 184.4 281.2 567.5 129.2* 63.8 group rich feed Err. #2.3 #3.5 #29.8 #5.4 #14.4 with +
Sample b Sample b
Notes: Av. means average and Err. means standard error.
*The significance was tested against the Control group with 5% level of significance and judged significant.
TABLE 3
Serum P-lipo- Liver Total Liver
protein Liver Weight Cholesterol Lipids
(mg/dl) (9/100 g b.w.) (mg/g) (mg/g)
Normal Ave. 113.4 4.756 2.51 37.0
group Err. +10.0 +0.248 it.16 +1.3
Control Ave. 526,6 5.366 40.11 101.8
group Err. +52.9 *0.141 +3.08 +10.0
Test Ave. 213.6* 4.936* 14.44* 63,7*
group Err. +23.3 +0.118 +2.32 +3.8
with
Sample a
Test Ave. 202.6* 4.855* 17.67* 67.1*
group Err. +11.9 +0.136 *2.46 +3.7
with
Sample b
Notes: Ave. means average and Err. means standard error.
* The significance was tested against the Control group with 5% level of significance
and judged significant.
The arteriosclerosis treating agents in accordance with the present invention are believed to have various usefulnesses in the treatment and prevention of various kinds of diseases due to high blood lipids closely related to arteriosclerosis. For example, as shown in Test Example 1, as the result of comparing Samples a and b of the present invention with Samples d and c of Reference Examples 1 and 2, respectively, it can be seen that at pH = 7.00 simulating that of the intestinal juice which is thought to be the site of action of the cholesterol absorption inhibiting agents, Samples a and b exhibit excellent adsorptivity of cholic acid approximately 1.4 to 1.5 times as much as those of comparison.
In addition, as the result of the test on rats as shown in Test Example 2, it can be seen that
Samples a and b, as compared with the Control group, remarkably exhibit the effect to reduce high
blood lipids such as serum cholesterol, serum triglyceride, serum p-lipoprotein, liver cholesterol, liver
lipids, etc. closely related to arteriosclerosis.
While in the case of lipidemia high level of serum triglyceride is generally observed, it is reported
that commercial cholesterol absorption inhibiting drugs do not effect on the serum triglyceride level (see
Yakkyoku, 25(7), 1133 (1 974)). As shown in Test Example 2, Sample b of the present invention also
exhibits an excellent effect to reduce the serum triglyceride level to the normal level.
Taking into consideration that this type of cholesterol absorption inhibiting drug is to be
administered in large dosages for a prolonged period from the nature of the drug, it is quite important
from the clinical point of view that each dose is small and side effects are little, which therefore
indicates that the polymer compounds in accordance with the present invention possess great
usefulness.
While the invention has been described in detail and with reference to specific embodiments
thereof, it will be apparent to one skilled in the art that various changes and modifications can be made
therein without departing from the scope thereof.
Claims (2)
1. A polymer compound which is a crosslinked polymer obtained from a nitrogen-containing compound selected from ammonia, ethylediamine and a polyethylene polyamine having a degree of repeating units of 2-1 500, and a bifunctional compound of the formula: : Y-M-Z wherein Y represents a -CH2X group (wherein X represents a chlorine, bromine or iodine atom) or a
group, M represents a single bond, a (CH2)m-group (wherein m represents 1,2 or 3), a -CH2-0-CH2- group or a-CH2-O-(CH2)k-O-CH2-group (wherein k represents 1, 2, 3 or 4) and Z represents a -CH(OH)-CH2X group (wherein X is the same as hereinbefore defined) or a
group, 20 percent or more of the nitrogen atoms of which are combined with lower alkyl groups to form
a quaternary ammonium salt; or a pharmaceutically acceptable non-toxic salt thereof.
1 9. An arteriosclerosis agent substantially as hereinbefore described in Example 3 or 4.
20. A process as claimed in claim 8, substantially as hereinbefore described in Example 1 or
2.
21. A cross-linked polymer compound when produced by the process as claimed in any one of claims 8 to 1 6 or claim 20.
22. A compound as claimed in any one of claims 1 t6 7 or claim 18 for use in a method of treatment of arteriosclerosis.
New claims or amendments to claims filed on 1 7th March 1980.
Superseded claims 1.
New or amended claims:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13934678A JPS5566513A (en) | 1978-11-14 | 1978-11-14 | Drug for arteriosclerosis comprising high polymer compound as active constituent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2036048A true GB2036048A (en) | 1980-06-25 |
| GB2036048B GB2036048B (en) | 1983-05-05 |
Family
ID=15243181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7939305A Expired GB2036048B (en) | 1978-11-14 | 1979-11-13 | Polymer compounds process for their preparation and arterio-sclerosis treating agents containing them |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5566513A (en) |
| DE (1) | DE2946026A1 (en) |
| FR (1) | FR2441639A1 (en) |
| GB (1) | GB2036048B (en) |
| IT (1) | IT7950802A0 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4528184A (en) * | 1981-11-04 | 1985-07-09 | Kabushiki Kaisha Vitamin Kenkyuso | Polymer-metal complexes containing quaternary nitrogen atoms used in the treatment of hypercholesteremia |
| WO1995034585A1 (en) * | 1994-06-10 | 1995-12-21 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| US5496545A (en) * | 1993-08-11 | 1996-03-05 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
| US5556619A (en) * | 1992-08-20 | 1996-09-17 | The Du Pont Merck Pharmaceutical Company | Crosslinked polymeric ammonium salts |
| US5633344A (en) * | 1992-08-20 | 1997-05-27 | E. I. Du Pont De Nemours & Company | Crosslinked polymeric ammonium salts |
| US5874522A (en) * | 1992-08-20 | 1999-02-23 | Dupont Pharmaceuticals Company | Crosslinked polymeric ammonium salts |
| WO2000064428A2 (en) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
| US6509013B1 (en) | 1993-08-11 | 2003-01-21 | Geltex Pharmaceuticals, Inc. | Method of making phosphate-binding polymers for oral administration |
| US7985418B2 (en) | 2004-11-01 | 2011-07-26 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| US8187631B2 (en) | 1999-10-19 | 2012-05-29 | Genzyme Corporation | Direct compression polymer tablet core |
| US9095509B2 (en) | 2005-09-15 | 2015-08-04 | Genzyme Corporation | Sachet formulation for amine polymers |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3901527A1 (en) * | 1989-01-20 | 1990-07-26 | Hoechst Ag | ALKYLATED POLYETHYLENE IMIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND PHARMACEUTICAL PREPARATIONS |
| AT409629B (en) * | 2000-09-14 | 2002-09-25 | Dsm Fine Chem Austria Gmbh | WASHING METHOD FOR CLEANING N-BZW. POLYMERS CONTAINING AMINO OR AMMONIUM GROUPS |
| EP1951266A2 (en) | 2005-09-02 | 2008-08-06 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
-
1978
- 1978-11-14 JP JP13934678A patent/JPS5566513A/en active Pending
-
1979
- 1979-11-12 IT IT7950802A patent/IT7950802A0/en unknown
- 1979-11-13 FR FR7927955A patent/FR2441639A1/en active Pending
- 1979-11-13 GB GB7939305A patent/GB2036048B/en not_active Expired
- 1979-11-14 DE DE19792946026 patent/DE2946026A1/en not_active Withdrawn
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4528184A (en) * | 1981-11-04 | 1985-07-09 | Kabushiki Kaisha Vitamin Kenkyuso | Polymer-metal complexes containing quaternary nitrogen atoms used in the treatment of hypercholesteremia |
| US5556619A (en) * | 1992-08-20 | 1996-09-17 | The Du Pont Merck Pharmaceutical Company | Crosslinked polymeric ammonium salts |
| US5633344A (en) * | 1992-08-20 | 1997-05-27 | E. I. Du Pont De Nemours & Company | Crosslinked polymeric ammonium salts |
| US5726284A (en) * | 1992-08-20 | 1998-03-10 | The Dupont Merck Pharmaceutical Company | Crosslinked polymric ammonium salts |
| US5874522A (en) * | 1992-08-20 | 1999-02-23 | Dupont Pharmaceuticals Company | Crosslinked polymeric ammonium salts |
| US6509013B1 (en) | 1993-08-11 | 2003-01-21 | Geltex Pharmaceuticals, Inc. | Method of making phosphate-binding polymers for oral administration |
| US7459151B2 (en) | 1993-08-11 | 2008-12-02 | Genzyme Corporation | Phosphate-binding polymers for oral administration |
| US5496545A (en) * | 1993-08-11 | 1996-03-05 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
| US7014846B2 (en) | 1993-08-11 | 2006-03-21 | Genzyme Corporation | Phosphate-binding polymers for oral administration |
| US6858203B2 (en) | 1993-08-11 | 2005-02-22 | Genzyme Corporation | Method of making phosphate-binding polymers for oral administration |
| US6784254B2 (en) | 1994-06-10 | 2004-08-31 | Genzyme Corporation | Process for removing bile salts from a patient and alkylated compositions therefor |
| US7101960B2 (en) | 1994-06-10 | 2006-09-05 | Genzyme Corporation | Process for removing bile salts from a patient and alkylated compositions therefor |
| WO1995034585A1 (en) * | 1994-06-10 | 1995-12-21 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| US7399821B2 (en) | 1994-06-10 | 2008-07-15 | Genzyme Corporation | Alkylated poly(allylamine) polymers and methods of use |
| EP0909768A3 (en) * | 1994-06-10 | 2001-01-17 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| US6433026B2 (en) | 1994-06-10 | 2002-08-13 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| EP0909768A2 (en) * | 1994-06-10 | 1999-04-21 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| WO2000064428A2 (en) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
| US6517825B1 (en) | 1999-04-23 | 2003-02-11 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
| WO2000064428A3 (en) * | 1999-04-23 | 2001-02-08 | Geltex Pharma Inc | Polyether-based bile acid sequestrants |
| US8187631B2 (en) | 1999-10-19 | 2012-05-29 | Genzyme Corporation | Direct compression polymer tablet core |
| US9579343B2 (en) | 1999-10-19 | 2017-02-28 | Genzyme Corporation | Direct compression polymer tablet core |
| US9931358B2 (en) | 1999-10-19 | 2018-04-03 | Genzyme Corporation | Direct compression polymer tablet core |
| US7985418B2 (en) | 2004-11-01 | 2011-07-26 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| US8808738B2 (en) | 2004-11-01 | 2014-08-19 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| US9555056B2 (en) | 2004-11-01 | 2017-01-31 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| US9895315B2 (en) | 2004-11-01 | 2018-02-20 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
| US9095509B2 (en) | 2005-09-15 | 2015-08-04 | Genzyme Corporation | Sachet formulation for amine polymers |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5566513A (en) | 1980-05-20 |
| IT7950802A0 (en) | 1979-11-12 |
| FR2441639A1 (en) | 1980-06-13 |
| GB2036048B (en) | 1983-05-05 |
| DE2946026A1 (en) | 1980-07-10 |
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| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |