CA1050035A - Polymers containing polyunsaturated acid radicals, process for their preparation and use therof - Google Patents
Polymers containing polyunsaturated acid radicals, process for their preparation and use therofInfo
- Publication number
- CA1050035A CA1050035A CA237,711A CA237711A CA1050035A CA 1050035 A CA1050035 A CA 1050035A CA 237711 A CA237711 A CA 237711A CA 1050035 A CA1050035 A CA 1050035A
- Authority
- CA
- Canada
- Prior art keywords
- polyacrylic
- polymethacrylic
- prepared
- radicals
- prostaglandins
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/14—Esterification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/10—Acylation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
-
- 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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to polymers having a molecular weight between 1000 and 1,500,000, characterized in that they contain polyunsaturated acids radicals with 20 carbon atoms bound to a macromolecular backbone of polyacrylic or polymeth-acrylic units through ester or amide bonds, which radicals are gradually hydrolized in a biological system while forming prostaglandins and leaving non-toxic polymeric residues.
This invention relates to polymers having a molecular weight between 1000 and 1,500,000, characterized in that they contain polyunsaturated acids radicals with 20 carbon atoms bound to a macromolecular backbone of polyacrylic or polymeth-acrylic units through ester or amide bonds, which radicals are gradually hydrolized in a biological system while forming prostaglandins and leaving non-toxic polymeric residues.
Description
~(~5i~ 3S
1 The present invention reEers to new polymers character-ized by the presence of polyunsaturated acid radicals with 20 carbon atoms bound to the polymeric matrix in such a way to be hydrolized in biological systems while forming prostaglandins.
More precisely, the present invention concerns high polymers containing radicals of the eicosatrienoic, eicosatetra-enoic, eicosapentenoic acids bound to the macromolecular matrix by ester or amide bonds, which radicals are gradually hydrolyzed in a predetermined way in biological systems and contemoraneously cyclized to give free prostaglandins.
It is well known that prostaglandins represen~ one of the most interesting developments in the biomedical field during last years.
From the chemical point of view prostaglandins are essentially polyunsaturated hydroxy acids with a skeleton of 20 carbon atoms partially cyclized-: to form a ring of 5 carbon -atoms. Prostaglandins have been classified in several series of which two have significant biomedical effect. These two major series differ only because one (PGF) contains two hydroxyl groups in the 5 carbon atom ring, and the other (PGE), a keto group and a hydroxyl group in the same ring. Subclasses are also known characterized by the presence of a double bond in a fixed position or by the presence of more than one double bond. In all cases prostaglandins present a carboxyl and at least one hydroxyl group free to react.
Prostaglandins are formed in the body starting from long-chain polyunsaturated fatty acids, essentially 8/ 11, 14-eiconsatrienoic acid, 5, 8, 11, 14-eicosatetraenoic acid, and 5, 8, 11, 14, 17-eicosapentenoic acid, released by specific enzymatic reactions from tissue lipids.
--1-- ,~ :
,~
1 According to recent studies, prostaglandins are responsible in the organism oE a great variety of physiological and pharmacological effects,from fertility control to stimulation of smooth muscle contraction, regulation of arterial pressure, platelets aggregation, gastric secretion.
From the practical point of ~iew, a considerable body of published evidence demonstrates that protaglandins are of use to solve the problem of birth control, as preventing agents if administered at approriate time and doses, or by inducing abortion.
However, the great hopes in this field have been partially non-substantiated by a practical use of prostaglandins, due to the insurgence of collateral effects which connot be eliminated or controlled. For example, in order to obtain the desired effect of fertility control or abortion induction, prostaglandins should be given at such large doses and for such prolonged periods, that other biological effects of prostaglandins become evident, as the induction of hypotensive or hypertermic crisis/ intestinal smooth muscle contractions and thus vomit and diarrhea, headache, decrease of the pain threshold in muscles and articulations and platelets aggregation.
We have unexpectedly found that new polymers may be synthesized containing the radicals of the polyunsaturated acids precursors of protaglandins in the organism bound to the macromolecular matrix by covalent bonds of esteric or amidic type.
Such polymers in biological systems are gradually hydrolysed releasing predetermined amounts of acids during predetermined time intervals, which acids are immediately transformed by the organism to prostanglandins. Such polymer classes are non toxic for mammalian organisms, give rise to non toxic metabolites and can be predesigned from the point of view ~O~i()035 1 of the chemical nature, of ~he molecular weight, of the percentage of acid radicals contained in the macromolecular complex and of the type of chemical bonds through which these radicals are bound to the macromolecular matrix. This may be done in such a way to insure the presence in blood and tissues of strictly controlled concentrations of prostaglandins for the desirPd time intervals.
The presence of excess prostaglandins is therefore avoided and undesirahle side effects due to prostaglandins and/or to their metabolites can be prevented or strongly reduced.
~ ur new polymers are characterized by a polyvinyl backbone to which said polyunsaturated acid radicals are bound by covalent, esteric or amidic ~onds either directly or through side chains.
Preferably the fundamental polyvinylic structure is a polymer of acrylamide, methacrylamide, acrylic acid or methacrylic acid.
These new polymers, according to the invention, are preferably prepared by:
a) preparation of acrylic monomers containing reactive groups chosen in the group consisting of l-acryloilbenzotriazole, l-acryloil methoxybenzotriazole, l-acryloilmethylbenzotriazole, l-acryloil imidazole, N-acryloilsuccinimide and N-2,4,5-trichloro-phenylacrylamide: homopolymerization of these monomers or their copolymerization with different vinylic monomers; reaction of the above polymers or copolymers with the polyunsaturated acids through the reactive groups of the polymeric matrix;
b) homopolymerization of acrylic acid or its copolymerization with other vinylic monomers; reaction of these polymers or copolymers with carbonyldiimidazole in order to introduce reactive . .
1 groups of acetylimida~clide type; reaction of these macro-molecular substances with the polyunsaturated acids;
c) preparation of homopolymers or copolymers containing reactive groups as indicated under (a); reaction of these macromolecular substances with. alkylene-diamines, hydroxyalkylamines or alkylene dihydroxy compounds in order to obtain side chains containing reactive hydroxylor amminic groups; reactions of these new macromolecular substances with the polyunsaturated acids.
The macromolecular matrix is prepared with a determined percentage of reactive groups according to the desired percentage of polyunsaturated acids in the final product. The new polymers with a fundamental polymethacrylic structure are more slowly hydrolyzed than the corresponding acrylic polymers and therefore they release more slowly the prostaglandins acid precursors thus prolonging prostaglandins biological activity and reducing their side effects.
The polymers, according to the invention may be water soluble or insoluble (oil insoluble) and can be prepared in form of hydrophylic, but water insoluble gels..
If water soluble polymers are desired, hydrophylic monomers must be used, particularly monomers selected in the group comprising l-acryloil-.4-methyl piperazine, N~acryloil morpholine, N-~inylpyrolidone which copolymerise smoothly and with almost quantitative yields with the activated acrylic monomers.
. The same monomers are used if hydrophylic gels are desired, but in this case difunctional comonomers are added, in the range of 0.5 to 30~ in order to obtain a crosslinked product.
These difunctional monomers are preferably chosen from the group 1 comprising divinylbenzene or bis-acrylamides such as methylene bis acrylamide, N,N~-bisacrylOil piperazine of N~N'~bisacryloil N,N'-dimethylethylene diamine.
The new polymers, according to the invention, can be administered with any procedure already in use for the ree prostaglandins and particularly by intravenous, intraamniotic, intrauterine or intravaginal routes.
Some pharmacological data are here reported in order to underline the practical advantages obtainable by using the new prostaglandin precursors releasing polymers in comparison with the use of corresponding amounts of free prostaglandins.
The experiments have been carried out by usiny anesthetized cats weighing 2.100 kg. Anaesthesia has been induced with ethyl ether and maintained with a solution of choralase and urethane (80:100) given intravenously through the femoral vein.
Then trachea and one femoral artery are cannulated for pressure registration. A baloon is introduced in the stomach for the direct registration of smooth muscle motility. The results are summarized in the following table. -The polymer employed is prepared as described in example n. l(A).
3~
o~ ^
o a) O ~ ~ ~D 00 a:) ~ ~ ~ ~1 tq U~
o.l.
~ ~0 t~
(~ N N N O
~ ~o3 ::~E3 's~ ~5 0~
~tq . ~ ~ ~ o h h ~:
.., a ~; ,~
O' O
~ ~ ''' ,a~ ,~
u t~ 3 ~ u~ o . ~ O ~ C) O
0 S-l h h rd h ~, ~ ~ ~ ~ h ~
. ~ ~ ~ :~ ~ Ql a) ./ h ~I b~ P;
~ ~ O ~ O ~ O s:
E~ ~ ~-~
.
.
, ~C~5~
1 The reported data show that by causing the formation of prostaglandins directly in the organism, through administration of high polymers containing radicals o~ polyunsaturated acids which are prostaglandins precursors, and controlling through the releasing of the acids radicals the amounts and the administration time of prostaglandins, it has become possible t~ prolong the pharmacological duration of effect while no side-effect i5 observed and effects are evidentiated which are not and cannot be observed with the same doses of the free drug.
lQ EXAMPLE
a) A mixture consisting of 1 g of l-acryloilbenzotriazole, 9 g of 1-acryloil-4-methyl-piperazine, 100 mg of azodiisobutyl-onitrile and 50 ml of anhydrous dioxane is heated at 60C over 40 hours, under argon atmosphere.
The reacted mixture is poured into one liter of anhydrous ethylic ether and a polymer separates, with nearly 100~ yield, which contains 10~ by weight o~ acryloilbenzotriazole.
b) 1 g of the above copolymer is dissolved in 10 ml anhydrous, alcohol-free chloroform. To this solution, a solution of N,N-dihydroxyethyl-1~3-diaminopropane (0.25 g) in
1 The present invention reEers to new polymers character-ized by the presence of polyunsaturated acid radicals with 20 carbon atoms bound to the polymeric matrix in such a way to be hydrolized in biological systems while forming prostaglandins.
More precisely, the present invention concerns high polymers containing radicals of the eicosatrienoic, eicosatetra-enoic, eicosapentenoic acids bound to the macromolecular matrix by ester or amide bonds, which radicals are gradually hydrolyzed in a predetermined way in biological systems and contemoraneously cyclized to give free prostaglandins.
It is well known that prostaglandins represen~ one of the most interesting developments in the biomedical field during last years.
From the chemical point of view prostaglandins are essentially polyunsaturated hydroxy acids with a skeleton of 20 carbon atoms partially cyclized-: to form a ring of 5 carbon -atoms. Prostaglandins have been classified in several series of which two have significant biomedical effect. These two major series differ only because one (PGF) contains two hydroxyl groups in the 5 carbon atom ring, and the other (PGE), a keto group and a hydroxyl group in the same ring. Subclasses are also known characterized by the presence of a double bond in a fixed position or by the presence of more than one double bond. In all cases prostaglandins present a carboxyl and at least one hydroxyl group free to react.
Prostaglandins are formed in the body starting from long-chain polyunsaturated fatty acids, essentially 8/ 11, 14-eiconsatrienoic acid, 5, 8, 11, 14-eicosatetraenoic acid, and 5, 8, 11, 14, 17-eicosapentenoic acid, released by specific enzymatic reactions from tissue lipids.
--1-- ,~ :
,~
1 According to recent studies, prostaglandins are responsible in the organism oE a great variety of physiological and pharmacological effects,from fertility control to stimulation of smooth muscle contraction, regulation of arterial pressure, platelets aggregation, gastric secretion.
From the practical point of ~iew, a considerable body of published evidence demonstrates that protaglandins are of use to solve the problem of birth control, as preventing agents if administered at approriate time and doses, or by inducing abortion.
However, the great hopes in this field have been partially non-substantiated by a practical use of prostaglandins, due to the insurgence of collateral effects which connot be eliminated or controlled. For example, in order to obtain the desired effect of fertility control or abortion induction, prostaglandins should be given at such large doses and for such prolonged periods, that other biological effects of prostaglandins become evident, as the induction of hypotensive or hypertermic crisis/ intestinal smooth muscle contractions and thus vomit and diarrhea, headache, decrease of the pain threshold in muscles and articulations and platelets aggregation.
We have unexpectedly found that new polymers may be synthesized containing the radicals of the polyunsaturated acids precursors of protaglandins in the organism bound to the macromolecular matrix by covalent bonds of esteric or amidic type.
Such polymers in biological systems are gradually hydrolysed releasing predetermined amounts of acids during predetermined time intervals, which acids are immediately transformed by the organism to prostanglandins. Such polymer classes are non toxic for mammalian organisms, give rise to non toxic metabolites and can be predesigned from the point of view ~O~i()035 1 of the chemical nature, of ~he molecular weight, of the percentage of acid radicals contained in the macromolecular complex and of the type of chemical bonds through which these radicals are bound to the macromolecular matrix. This may be done in such a way to insure the presence in blood and tissues of strictly controlled concentrations of prostaglandins for the desirPd time intervals.
The presence of excess prostaglandins is therefore avoided and undesirahle side effects due to prostaglandins and/or to their metabolites can be prevented or strongly reduced.
~ ur new polymers are characterized by a polyvinyl backbone to which said polyunsaturated acid radicals are bound by covalent, esteric or amidic ~onds either directly or through side chains.
Preferably the fundamental polyvinylic structure is a polymer of acrylamide, methacrylamide, acrylic acid or methacrylic acid.
These new polymers, according to the invention, are preferably prepared by:
a) preparation of acrylic monomers containing reactive groups chosen in the group consisting of l-acryloilbenzotriazole, l-acryloil methoxybenzotriazole, l-acryloilmethylbenzotriazole, l-acryloil imidazole, N-acryloilsuccinimide and N-2,4,5-trichloro-phenylacrylamide: homopolymerization of these monomers or their copolymerization with different vinylic monomers; reaction of the above polymers or copolymers with the polyunsaturated acids through the reactive groups of the polymeric matrix;
b) homopolymerization of acrylic acid or its copolymerization with other vinylic monomers; reaction of these polymers or copolymers with carbonyldiimidazole in order to introduce reactive . .
1 groups of acetylimida~clide type; reaction of these macro-molecular substances with the polyunsaturated acids;
c) preparation of homopolymers or copolymers containing reactive groups as indicated under (a); reaction of these macromolecular substances with. alkylene-diamines, hydroxyalkylamines or alkylene dihydroxy compounds in order to obtain side chains containing reactive hydroxylor amminic groups; reactions of these new macromolecular substances with the polyunsaturated acids.
The macromolecular matrix is prepared with a determined percentage of reactive groups according to the desired percentage of polyunsaturated acids in the final product. The new polymers with a fundamental polymethacrylic structure are more slowly hydrolyzed than the corresponding acrylic polymers and therefore they release more slowly the prostaglandins acid precursors thus prolonging prostaglandins biological activity and reducing their side effects.
The polymers, according to the invention may be water soluble or insoluble (oil insoluble) and can be prepared in form of hydrophylic, but water insoluble gels..
If water soluble polymers are desired, hydrophylic monomers must be used, particularly monomers selected in the group comprising l-acryloil-.4-methyl piperazine, N~acryloil morpholine, N-~inylpyrolidone which copolymerise smoothly and with almost quantitative yields with the activated acrylic monomers.
. The same monomers are used if hydrophylic gels are desired, but in this case difunctional comonomers are added, in the range of 0.5 to 30~ in order to obtain a crosslinked product.
These difunctional monomers are preferably chosen from the group 1 comprising divinylbenzene or bis-acrylamides such as methylene bis acrylamide, N,N~-bisacrylOil piperazine of N~N'~bisacryloil N,N'-dimethylethylene diamine.
The new polymers, according to the invention, can be administered with any procedure already in use for the ree prostaglandins and particularly by intravenous, intraamniotic, intrauterine or intravaginal routes.
Some pharmacological data are here reported in order to underline the practical advantages obtainable by using the new prostaglandin precursors releasing polymers in comparison with the use of corresponding amounts of free prostaglandins.
The experiments have been carried out by usiny anesthetized cats weighing 2.100 kg. Anaesthesia has been induced with ethyl ether and maintained with a solution of choralase and urethane (80:100) given intravenously through the femoral vein.
Then trachea and one femoral artery are cannulated for pressure registration. A baloon is introduced in the stomach for the direct registration of smooth muscle motility. The results are summarized in the following table. -The polymer employed is prepared as described in example n. l(A).
3~
o~ ^
o a) O ~ ~ ~D 00 a:) ~ ~ ~ ~1 tq U~
o.l.
~ ~0 t~
(~ N N N O
~ ~o3 ::~E3 's~ ~5 0~
~tq . ~ ~ ~ o h h ~:
.., a ~; ,~
O' O
~ ~ ''' ,a~ ,~
u t~ 3 ~ u~ o . ~ O ~ C) O
0 S-l h h rd h ~, ~ ~ ~ ~ h ~
. ~ ~ ~ :~ ~ Ql a) ./ h ~I b~ P;
~ ~ O ~ O ~ O s:
E~ ~ ~-~
.
.
, ~C~5~
1 The reported data show that by causing the formation of prostaglandins directly in the organism, through administration of high polymers containing radicals o~ polyunsaturated acids which are prostaglandins precursors, and controlling through the releasing of the acids radicals the amounts and the administration time of prostaglandins, it has become possible t~ prolong the pharmacological duration of effect while no side-effect i5 observed and effects are evidentiated which are not and cannot be observed with the same doses of the free drug.
lQ EXAMPLE
a) A mixture consisting of 1 g of l-acryloilbenzotriazole, 9 g of 1-acryloil-4-methyl-piperazine, 100 mg of azodiisobutyl-onitrile and 50 ml of anhydrous dioxane is heated at 60C over 40 hours, under argon atmosphere.
The reacted mixture is poured into one liter of anhydrous ethylic ether and a polymer separates, with nearly 100~ yield, which contains 10~ by weight o~ acryloilbenzotriazole.
b) 1 g of the above copolymer is dissolved in 10 ml anhydrous, alcohol-free chloroform. To this solution, a solution of N,N-dihydroxyethyl-1~3-diaminopropane (0.25 g) in
2.5 ml chloroform is added. The reaction mixture is left at room temperature for 24 hours with occasional shaking. The product is then isolated by pouring the reaction mixture into 200 ml of anhydrous ether. The precipitate is collected, dissolved in chloroform (25 ml), the solution again poured into 300 ml of dry ether, and the precipitated product collected and dried at room temperature and 0.01 mm~g. The yield is practically quantitative.
c) A solution of the above product (0.5 g) in dry, alcohol-free chloroform (2OS ml) is prepared (solution a).
~0'50~3~
1 Arachidonic acid (0.2833 g) is dissolved in dry, alcohol-free chloroform (2.5 ml), and N,N-carbonyldiimidazole (0.119 g) added to this mixture (solution b).
The solution b) is left at room temperature for 1 hour, with occasional shaking and then the solution a) is added to it under stirring; the resulting mixture is left at 60C for 24 hours under inert gas atmosphere. The product is then isolated by pouring the reaction mixture into an excess of dry ether. The precipitate is collected, washed with ether and dried at room temperature and 0.001 mmHg. A practically quantitative yield of a copolymer containing 14.6~ by weight of arachidonic acid which could be entirely xeleased in biological environments, is obtained.
EXAMPLE _ The same procedure was followed as in the pre~ious case, but di-homo-~-linolenic acid was substituted for arachidonic acid. The product was isolated in the same way, and it contained about 14.4% by weight of di-homo-~ -linolenic acid. The yield was practically quantitative.
a) Starting from 2 g of l-acryloilbenzotriazole and 8 of l-acryloil-4-methyl piperazine, and following the same procedure as described in the example l(a), a copolymer was prPpared containing 20% by weight of l-acryloilbenæotriazole units.
b) 5 g of the above copolymer we~e dissolved in 50 ml of anhydrous dimethylformamide. Ethanolamine (0.353 g) was then added, and the reaction mixture was stirred at room temperature for 24 hrs. (solution a~. Di-homo-~ -linolenic acid ~1.595 g) was dissolved in anhydrous dimethylformamide (5 ml) and to this ~OSCI~35 1 solution, 0.936 g of N~ carbonyldiimidazole were added under vigorous stirring. The solution was then stirred for 1 hour at room temperature (solution b).
Solutions a) and b) were then admixed, and left at 60C for 24 hours with occasional stirring. The reaction mixture was pouxed into an excess of ether, and the precipitate was filtered or centrifuged, dissolved in chloroform and repre-ipi~ated in ether to give about 5.5 g of a product containing 10.2~ of di-homo- ~-linolenic acid which could be entirely released in a biological environment.
Exactly reproducing the preparation method described in Example 1, copolymers have been prepared containing various percentages of hydrolyzable arachidonic acid, starting from acrylic copolymers containing corresponding percentages of 1-acryloilbenzotriazole.
- Following the procedure described in Example 2, copolymers have been prepared containing various percentages of hydrolyza~le di-homo-~ -linolenic acid, starting from acrylic copolymers containing corresponaing percentages of l-acryloil-benzotriazole.
c) A solution of the above product (0.5 g) in dry, alcohol-free chloroform (2OS ml) is prepared (solution a).
~0'50~3~
1 Arachidonic acid (0.2833 g) is dissolved in dry, alcohol-free chloroform (2.5 ml), and N,N-carbonyldiimidazole (0.119 g) added to this mixture (solution b).
The solution b) is left at room temperature for 1 hour, with occasional shaking and then the solution a) is added to it under stirring; the resulting mixture is left at 60C for 24 hours under inert gas atmosphere. The product is then isolated by pouring the reaction mixture into an excess of dry ether. The precipitate is collected, washed with ether and dried at room temperature and 0.001 mmHg. A practically quantitative yield of a copolymer containing 14.6~ by weight of arachidonic acid which could be entirely xeleased in biological environments, is obtained.
EXAMPLE _ The same procedure was followed as in the pre~ious case, but di-homo-~-linolenic acid was substituted for arachidonic acid. The product was isolated in the same way, and it contained about 14.4% by weight of di-homo-~ -linolenic acid. The yield was practically quantitative.
a) Starting from 2 g of l-acryloilbenzotriazole and 8 of l-acryloil-4-methyl piperazine, and following the same procedure as described in the example l(a), a copolymer was prPpared containing 20% by weight of l-acryloilbenæotriazole units.
b) 5 g of the above copolymer we~e dissolved in 50 ml of anhydrous dimethylformamide. Ethanolamine (0.353 g) was then added, and the reaction mixture was stirred at room temperature for 24 hrs. (solution a~. Di-homo-~ -linolenic acid ~1.595 g) was dissolved in anhydrous dimethylformamide (5 ml) and to this ~OSCI~35 1 solution, 0.936 g of N~ carbonyldiimidazole were added under vigorous stirring. The solution was then stirred for 1 hour at room temperature (solution b).
Solutions a) and b) were then admixed, and left at 60C for 24 hours with occasional stirring. The reaction mixture was pouxed into an excess of ether, and the precipitate was filtered or centrifuged, dissolved in chloroform and repre-ipi~ated in ether to give about 5.5 g of a product containing 10.2~ of di-homo- ~-linolenic acid which could be entirely released in a biological environment.
Exactly reproducing the preparation method described in Example 1, copolymers have been prepared containing various percentages of hydrolyzable arachidonic acid, starting from acrylic copolymers containing corresponding percentages of 1-acryloilbenzotriazole.
- Following the procedure described in Example 2, copolymers have been prepared containing various percentages of hydrolyza~le di-homo-~ -linolenic acid, starting from acrylic copolymers containing corresponaing percentages of l-acryloil-benzotriazole.
Claims (6)
1. Process for the preparation of non-toxic polymers having a molecular weight between 1000 and 1,500,000 containing polyun-saturated acids radicals with 20 carbon atoms which are gradually hydrolized in a biological system while forming prostaglandins and leaving non-toxic polymeric residues, wherein a polyacrylic or polymethacrylic macromolecular structure is prepared containing reactive groups and this structure is made to react with the simple or activated polyunsaturated acids directly or through previously grafted side-chains which contain reactive groups.
2. Process according to claim 1, wherein a polyacrylic or polymethacrylic macromolecular structure. containing activated ester or amide groups is prepared by homopolymerization or copolymerization of monomers preferably selected in the group comprising 1-acryloilbenzotriazole, 1-acryloilmethoxybenzotri-azole, 1-acryloilmethylbenzotriazole,1-acryloilimidazolide, N-acryloilsuccinimide, N-2,4,5-trichlorophenylacrylamide.
3. Process according to claim 1, wherein a polyacrylic or polymethacrylic structure containing activated amido groups is prepared by homopolymerization or copolymerization of acrylic or methacrylic acid and then reacting the thus obtained polymer with carbonyldiimidazole so as to introduce in the polyacrylic chain the reactive imidazolic groups.
4. Process according to claim 1 wherein the polyacrylic or polymethacrylic macromolecular structure is made to react, before reacting with the polyunsaturated acids, with alkylene-diamines, hydroxyalkylamines or glycols preferably selected in the group comprising N,N-dihydroxyethyl-1,3-propandiamine, ethanolamine, ethylendiamine, ethylenglycol.
5. Process according to claim 1, wherein the polyacrylic or polymethacrylic macromolecular structure is prepared by copolymerizing highly hydrophylic acrylic monomers with acrylic monomers containing reactive groups, said hydrophilic monomers being preferably selected in the group comprising 1-acryloil-4-methyl piperazine, N-acryloil-morpholine, N-vinylpirolidone.
6. Polymers having a molecular weight between 1000 and 1,500,000 whenever prepared by the process as claimed in claim 1, characterized in that they contain polyunsaturated acids radicals with 20 carbon atoms bound to a macromolecular backbone of polyacrylic or polymethacrylic units through ester or amide bonds, which radicals are generally hydrolized in a biological system while forming prostaglandins and leaving non-toxic polymeric residues.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT28419/74A IT1044797B (en) | 1974-10-15 | 1974-10-15 | HIGH POLYMERS CONTAINING PROSTAGLANDINIC RADICALS PROCESS FOR THEIR PREPARATION AND USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050035A true CA1050035A (en) | 1979-03-06 |
Family
ID=11223564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA237,711A Expired CA1050035A (en) | 1974-10-15 | 1975-10-15 | Polymers containing polyunsaturated acid radicals, process for their preparation and use therof |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US4228152A (en) |
| JP (2) | JPS51125497A (en) |
| AR (1) | AR213396A1 (en) |
| AT (1) | AT343899B (en) |
| BE (1) | BE834538A (en) |
| CA (1) | CA1050035A (en) |
| CH (1) | CH618190A5 (en) |
| DE (2) | DE2546241A1 (en) |
| DK (1) | DK461975A (en) |
| ES (1) | ES441756A1 (en) |
| FR (2) | FR2287913A1 (en) |
| GB (2) | GB1513410A (en) |
| IN (1) | IN142957B (en) |
| IT (1) | IT1044797B (en) |
| NL (1) | NL161462C (en) |
| SE (1) | SE7511468L (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2902955C2 (en) * | 1979-01-22 | 1982-09-16 | Escher Wyss AG, Zürich | Deflection adjustment roller |
| DE2902956C2 (en) * | 1979-01-23 | 1983-05-26 | Escher Wyss AG, Zürich | Heated deflection adjustment roller |
| US4675182A (en) * | 1983-02-12 | 1987-06-23 | Bayer Aktiengesellschaft | Complexes of prostaglandins |
| JPS60190722U (en) * | 1984-05-28 | 1985-12-17 | いすゞ自動車株式会社 | Work pitch feeding device |
| EP0172962A1 (en) * | 1984-08-30 | 1986-03-05 | Ono Pharmaceutical Co., Ltd. | Prostaglandins |
| JPS6279113A (en) * | 1985-09-30 | 1987-04-11 | Toyoda Gosei Co Ltd | Hose transporting device |
| US4684698A (en) * | 1986-05-02 | 1987-08-04 | Gaf Corporation | Water soluble multicomplex of chlorothiazide, furosemide and poly(N-vinyl-2-pyrrolidone) |
| WO1992001477A1 (en) * | 1990-07-26 | 1992-02-06 | G.D. Searle & Co. | Polymeric drug delivery system |
| FR2707010B1 (en) * | 1993-06-25 | 1995-09-29 | Bio Merieux | |
| ZA978537B (en) | 1996-09-23 | 1998-05-12 | Focal Inc | Polymerizable biodegradable polymers including carbonate or dioxanone linkages. |
| US6890524B1 (en) | 1997-04-04 | 2005-05-10 | Monsanto Company | Hydrolyzable delivery system using cross-linked polymeric resins as vehicles |
| AU6590598A (en) * | 1997-04-04 | 1998-10-30 | Monsanto Company | Hydrolysable delivery system using cross-linked polymeric resins as vehicles |
| WO1998044952A1 (en) | 1997-04-04 | 1998-10-15 | Monsanto Company | pH-SELECTIVE DELIVERY SYSTEM USING CROSS-LINKED POLYMERIC RESINS AS VEHICLES |
| JP4883515B2 (en) * | 1999-09-08 | 2012-02-22 | ポリセリックス リミテッド | Uniform molecular weight polymer |
| AU2001284092A1 (en) * | 2000-07-31 | 2002-02-13 | Bio Merieux | Succinimide derivative useful as polymerisable bifunctional monomer |
| US10113033B2 (en) | 2013-03-08 | 2018-10-30 | Polyactiva Pty Ltd | Polymer conjugate for delivery of a bioactive agent |
| KR102210895B1 (en) * | 2013-03-08 | 2021-02-02 | 폴리액티바 피티와이 리미티드 | Polymer conjugate for delivery of a bioactive agent |
| MX2019010837A (en) | 2017-03-14 | 2019-12-19 | Polyactiva Pty Ltd | Biodegradable drug-polymer conjugate. |
| US11207417B2 (en) | 2017-03-14 | 2021-12-28 | Polyactiva Pty Ltd | Drug-polymer conjugate |
| US11696955B2 (en) | 2017-03-14 | 2023-07-11 | Polyactiva Pty Ltd | Drug-polymer conjugate |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB869149A (en) * | 1958-09-16 | 1961-05-31 | Clinical Products Ltd | Liquid pharmaceutical compositions comprising compounds of ion exchange resins and therapeutic substances |
| FR1603393A (en) * | 1967-12-27 | 1971-04-13 | ||
| USRE28316E (en) | 1968-09-03 | 1975-01-21 | Entrapment compositions and processes | |
| US3932656A (en) * | 1970-09-10 | 1976-01-13 | Alza Corporation | Article of manufacture for instant release of anti-aggregation and non-thrombogenic agents to biological media |
| BE786747A (en) * | 1971-07-26 | 1973-01-26 | Du Pont | COPOLYMERS STATISTICAL GRAFTS OF PIVALOLACTONS |
| US4062855A (en) * | 1971-09-27 | 1977-12-13 | University Of Washington | Synthetic polymers furnishing controlled release of a biologically active component during degradation |
| US3898986A (en) * | 1972-12-27 | 1975-08-12 | Alza Corp | Biotransformable intrauterine device |
| US3811444A (en) * | 1972-12-27 | 1974-05-21 | Alza Corp | Bioerodible ocular device |
| US4145320A (en) * | 1974-10-15 | 1979-03-20 | Paolo Ferruti | Polymers containing polyunsaturated acid radicals, process for their preparation and use thereof |
-
1974
- 1974-10-15 IT IT28419/74A patent/IT1044797B/en active
-
1975
- 1975-10-10 GB GB41537/75A patent/GB1513410A/en not_active Expired
- 1975-10-10 IN IN1967/CAL/1975A patent/IN142957B/en unknown
- 1975-10-14 GB GB41991/75A patent/GB1524224A/en not_active Expired
- 1975-10-14 ES ES441756A patent/ES441756A1/en not_active Expired
- 1975-10-14 SE SE7511468A patent/SE7511468L/en not_active Application Discontinuation
- 1975-10-14 DK DK461975A patent/DK461975A/en not_active Application Discontinuation
- 1975-10-15 NL NL7512106.A patent/NL161462C/en not_active IP Right Cessation
- 1975-10-15 DE DE19752546241 patent/DE2546241A1/en not_active Ceased
- 1975-10-15 CA CA237,711A patent/CA1050035A/en not_active Expired
- 1975-10-15 JP JP50124258A patent/JPS51125497A/en active Granted
- 1975-10-15 FR FR7531529A patent/FR2287913A1/en active Granted
- 1975-10-15 FR FR7531530A patent/FR2287914A1/en active Granted
- 1975-10-15 AR AR260799A patent/AR213396A1/en active
- 1975-10-15 BE BE160960A patent/BE834538A/en unknown
- 1975-10-15 AT AT787075A patent/AT343899B/en not_active IP Right Cessation
- 1975-10-15 CH CH1337575A patent/CH618190A5/de not_active IP Right Cessation
- 1975-10-15 JP JP50124257A patent/JPS51125254A/en active Pending
- 1975-10-15 DE DE19752546240 patent/DE2546240A1/en not_active Withdrawn
-
1978
- 1978-11-14 US US05/960,665 patent/US4228152A/en not_active Expired - Lifetime
-
1979
- 1979-03-09 US US06/018,986 patent/US4223011A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51125254A (en) | 1976-11-01 |
| AT343899B (en) | 1978-06-26 |
| FR2287913B1 (en) | 1980-05-23 |
| US4223011A (en) | 1980-09-16 |
| FR2287913A1 (en) | 1976-05-14 |
| JPS543788B2 (en) | 1979-02-27 |
| ATA787075A (en) | 1977-10-15 |
| US4228152A (en) | 1980-10-14 |
| DE2546240A1 (en) | 1976-04-29 |
| SE7511468L (en) | 1976-04-20 |
| NL7512106A (en) | 1976-04-21 |
| AR213396A1 (en) | 1979-01-31 |
| BE834538A (en) | 1976-02-02 |
| ES441756A1 (en) | 1977-04-01 |
| CH618190A5 (en) | 1980-07-15 |
| GB1513410A (en) | 1978-06-07 |
| JPS51125497A (en) | 1976-11-01 |
| NL161462C (en) | 1980-02-15 |
| FR2287914B1 (en) | 1978-09-22 |
| IT1044797B (en) | 1980-04-21 |
| DK461975A (en) | 1976-04-16 |
| DE2546241A1 (en) | 1976-04-29 |
| NL161462B (en) | 1979-09-17 |
| IN142957B (en) | 1977-09-10 |
| FR2287914A1 (en) | 1976-05-14 |
| GB1524224A (en) | 1978-09-06 |
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