Patent US4888413A successfully refreshed from Google Patents.
US4888413A
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Poly(propylene glycol fumarate) compositions for biomedical applications
Assignee: Individual
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Filing: 1988-01-11
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Granted: 1989-12-19
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Expires: 2008-01-11
Abstract
Abstract The present invention are highly reproducible poly(propylene glycol fumarate) compositions having a controlled end group ratio and range of molecular weights with minimal low molecular weight and excessively high molecular weight fractions, and methods for their manufacture. These compositions, having a preferred weight average molecular weight (Mw) of between about 500 and 3000 and a number average molecular weight (Mn) of between about 300 and 2000, are especially useful in biomedical applications such as in bone cements and tissue implants or glues. In the preferred embodiment, the polymer is prepared from propylene glycol (PG) and fumaric acid (FA) by one of three methods: melt polymerization using non-volatile starting materials; step polymerization where in each step the polymer is increased by the addition of two groups to the polymer ends; or under reaction conditions maintained so that only the condensation byproduct, water, is removed during the reaction, thereby keeping the ratio between PG and FA constant. Variations of the PPF polymers include polymers with increased sensitivity to hydrolysis through incorporation of lactic acid groups into the polymer and polymers formed from maleic acid, maleic anhydride, citraconic acid or citraconic anhydride.
Inventors
- 👤 Abraham J. Domb
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 18:00
CPC Classifications
C; C08; C08G; C08G63/00; C08G63/02; C08G63/12; C08G63/52; A; A61; A61K; A61K9/00; A61K9/20; A61K9/2004; A61K9/2022; A61K9/2031; A61K9/204; A61L; A61L24/00; A61L24/001; A61L24/0042; A61L24/04; A61L24/046; A61L27/00; A61L27/14; A61L27/18; A61L27/50; A61L27/58; C08L; C08L67/00; C08L67/06; C08L2203/00; C08L2203/02
Claims Analysis
Total Claims: 48
Claim 1
Independent Claim
61 words
A biodegradable, biocompatible polymeric composition useful for repair of bone or tissue comprising: polymers of fumaric acid and propylene glycol having a preferred weight average molecular weight (Mw) of between about 500 and 3000 and a number average molecular weight (Mn) of between about 300 and 2000, and between 1 and 2 mmole carboxylic acid end groups per gram of polymer.
Claim 2
Dependent Claim
61 words
A biodegradable, biocompatible polymeric composition useful for repair of bone or tissue comprising: polymers of fumaric acid and propylene glycol having a preferred weight average molecular weight (Mw) of between about 500 and 3000 and a number average molecular weight (Mn) of between about 300 and 2000, and between 1 and 2 mmole carboxylic acid end groups per gram of polymer.
Claim 3
Dependent Claim
19 words
The polymeric composition of claim 1 having between 1.3 and 1.6 mmole carboxylic end groups per gram of polymer.
Claim 4
Dependent Claim
15 words
The polymeric composition of claim 1 having a mechanical strength between 5 and 40 mPa.
Claim 5
Dependent Claim
15 words
The polymeric composition of claim 3 having a mechanical strength between 10 and 25 MPa.
Claim 6
Dependent Claim
52 words
A poly(propylene glycol fumarate) polymeric composition having a number average molecular weight between about 300 and 2000 and a weight average molecular weight between 500 and 3000 wherein said composition is produced by ester melt condensation from diacid monomers and glycols which do not evaporate under melt condensation conditions of 180° C.
Claim 7
Dependent Claim
52 words
A poly(propylene glycol fumarate) polymeric composition having a number average molecular weight between about 300 and 2000 and a weight average molecular weight between 500 and 3000 wherein said composition is produced by ester melt condensation from diacid monomers and glycols which do not evaporate under melt condensation conditions of 180° C.
Claim 8
Dependent Claim
62 words
The polymeric composition of claim 5 formed by melt condensation of a compound selected from the group consisting of fumaric acid, bis-propylene glycol fumarate, 1,2 propylene glycol dibutenoate, propylene glycol oligomers having a molecular weight range between 100 and 5000, ethylene glycol oligomers having a molecular weight between 100 and 5000, maleic acid, maleic anhydride, citraconic acid, citraconic anhydride, and oligomers thereof.
Claim 9
Dependent Claim
45 words
The polymeric composition of claim 6 comprising the reaction product of fumaric acid and a compound selected from the group consisting of bis-propylene glycol fumarate and MPM pentamer at a ratio of 0.65:1 wherein said product contains minimal unreacted acid and has high mechanical strength.
Claim 10
Dependent Claim
20 words
The polymeric composition of claim 6 comprising the reaction product of PFP and MPM trimers at a ratio of 1:1.
Claim 11
Dependent Claim
35 words
The polymeric composition of claim 6 comprising the reaction product of MPM and PFP trimers with a compound selected from the group consisting of lactic acid or glycolic acid, said composition having lactic acid linkages.
Claim 12
Dependent Claim
114 words
A polymeric composition formed by step polymerizing trimers selected from the group consisting of bis-propylene glycol fumerate trimer, 1,2 propylene glycol dibutenoate (BPB and and MPM) trimer to form pentamers having carboxyl end groups; step polymerizing the product thereof to form heptamers having hydroxyl end groups; repeating the reactions of oligomers having carboxyl end groups to form longer oligomers having hydroxyl end groups and of oligomers having hydroxyl end groups to form longer oligomers having carboxyl end groups until polymers having between 1 and 2 mmole carboxylic acid end groups per gram of polymer and weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 13
Dependent Claim
114 words
A polymeric composition formed by step polymerizing trimers selected from the group consisting of bis-propylene glycol fumerate trimer, 1,2 propylene glycol dibutenoate (BPB and and MPM) trimer to form pentamers having carboxyl end groups; step polymerizing the product thereof to form heptamers having hydroxyl end groups; repeating the reactions of oligomers having carboxyl end groups to form longer oligomers having hydroxyl end groups and of oligomers having hydroxyl end groups to form longer oligomers having carboxyl end groups until polymers having between 1 and 2 mmole carboxylic acid end groups per gram of polymer and weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 14
Dependent Claim
120 words
A polymeric composition having a number average molecular weight of between about 300 and 2000 and a weight average molecular weight between 500 and 3000 wherein said composition is produced in two steps, first by polymerizing fumaric acid and propylene glycol at a temperature of between about 100° and 140° C. until the fumaric acid and propylene glycol form short polymers having weight average molecular weight of between 300 and 1000 and number average molecular weight between 200 and 600, then condensing the short polymers at a temperature between greater than 140° C. and 180° C. to form polymers having a weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 15
Dependent Claim
120 words
A polymeric composition having a number average molecular weight of between about 300 and 2000 and a weight average molecular weight between 500 and 3000 wherein said composition is produced in two steps, first by polymerizing fumaric acid and propylene glycol at a temperature of between about 100° and 140° C. until the fumaric acid and propylene glycol form short polymers having weight average molecular weight of between 300 and 1000 and number average molecular weight between 200 and 600, then condensing the short polymers at a temperature between greater than 140° C. and 180° C. to form polymers having a weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 16
Dependent Claim
45 words
A polymeric composition having a number average molecular weight of between about 300 and 2000 and a weight average molecular weight of between about 500 and 3000 wherein said composition is produced by polymerizing fumaric acid and propylene glycol in the presence of an azeotrope.
Claim 17
Dependent Claim
45 words
A polymeric composition having a number average molecular weight of between about 300 and 2000 and a weight average molecular weight of between about 500 and 3000 wherein said composition is produced by polymerizing fumaric acid and propylene glycol in the presence of an azeotrope.
Claim 18
Independent Claim
127 words
A method for producing a poly(propylene glycol fumarate) composition having a controlled number average molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: polymerizing by melt condensation compounds which do not evaporate under melt condensation conditions of 180° C. selected from the group consisting of bis-propylene glycol fumarate, oligomers of bis-propylene glycol fumarate, 1,2 propylene glycol dibutenoate, oligomers of 1,2 propylene glycol dibutenoate, oligomers of propylene glycol having a molecular weight range of between about 100 and 5000, and oligomers of ethylene glycol having a molecular weight range of between about 100 and 5000, with a compound selected from the group consisting of fumaric acid, oligomers of fumaric acid having carboxylic end groups, maleic acid, maleic anhydride, citraconic acid, and citraconic anhydride.
Claim 19
Independent Claim
127 words
A method for producing a poly(propylene glycol fumarate) composition having a controlled number average molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: polymerizing by melt condensation compounds which do not evaporate under melt condensation conditions of 180° C. selected from the group consisting of bis-propylene glycol fumarate, oligomers of bis-propylene glycol fumarate, 1,2 propylene glycol dibutenoate, oligomers of 1,2 propylene glycol dibutenoate, oligomers of propylene glycol having a molecular weight range of between about 100 and 5000, and oligomers of ethylene glycol having a molecular weight range of between about 100 and 5000, with a compound selected from the group consisting of fumaric acid, oligomers of fumaric acid having carboxylic end groups, maleic acid, maleic anhydride, citraconic acid, and citraconic anhydride.
Claim 20
Dependent Claim
26 words
The method of claim 13 further comprising controlling the molecular weight, polydispersity, and end groups by controlling the ratio of reactants, polymerization time, and polymerization temperature.
Claim 21
Dependent Claim
25 words
The method of claim 14 wherein the molecular weight of the resulting polymer is increased by polymerizing oligomers having higher molecular weights than the trimers.
Claim 22
Dependent Claim
27 words
The method of claim 13 further comprising increasing the mechanical strength of the resulting polymer by increasing the number of carboxyl end groups in the resulting polymer.
Claim 23
Dependent Claim
36 words
The method of claim 16 wherein the mechanical strength of the resulting polymer in a bone cement composition is increased by polymerizing starting materials with a higher ratio of carboxyl end groups to hydroxyl end groups.
Claim 24
Independent Claim
240 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: (a) step polymerizing bis-propylene glycol fumarate (PFP) trimer with maleic anhydride to form pentamers having carboxyl end groups and step polymerizing 1,2 propylene glycol dibutenoate (BPB and MPM) trimer with propylene oxide to form pentamers having hydroxyl end groups; (b) step polymerizing the pentamers formed by the reaction of bis-propylene glycol fumerate with maleic anhydride with propylene oxide to form heptamers having hydroxyl end groups and step polymerizing the pentamers formed by the reaction of 1,2 propylene glycol dibutenoate trimer with propylene oxide to form heptamers having carboxyl end groups; (c) step polymerizing heptamers formed by the reaction of the pentamers having hydroxyl end groups with maleic anhydride to form nonamers having carboxyl end groups and step polymerizing the heptamers formed by the reaction of the pentamers having the carboxyl end groups with propylene oxide to form nonamers having hydroxyl end groups; and (d) repeating the step polymerization of polymers having carboxyl end groups with propylene oxide to form longer polymers having hydroxyl groups and of polymers having hydroxyl groups with maleic anhydride to form longer polymers having carboxyl groups until polymers having between 1 and 2 mmole carboxylic acid end groups per gram of polymer and weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 25
Independent Claim
240 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: (a) step polymerizing bis-propylene glycol fumarate (PFP) trimer with maleic anhydride to form pentamers having carboxyl end groups and step polymerizing 1,2 propylene glycol dibutenoate (BPB and MPM) trimer with propylene oxide to form pentamers having hydroxyl end groups; (b) step polymerizing the pentamers formed by the reaction of bis-propylene glycol fumerate with maleic anhydride with propylene oxide to form heptamers having hydroxyl end groups and step polymerizing the pentamers formed by the reaction of 1,2 propylene glycol dibutenoate trimer with propylene oxide to form heptamers having carboxyl end groups; (c) step polymerizing heptamers formed by the reaction of the pentamers having hydroxyl end groups with maleic anhydride to form nonamers having carboxyl end groups and step polymerizing the heptamers formed by the reaction of the pentamers having the carboxyl end groups with propylene oxide to form nonamers having hydroxyl end groups; and (d) repeating the step polymerization of polymers having carboxyl end groups with propylene oxide to form longer polymers having hydroxyl groups and of polymers having hydroxyl groups with maleic anhydride to form longer polymers having carboxyl groups until polymers having between 1 and 2 mmole carboxylic acid end groups per gram of polymer and weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000.
Claim 26
Independent Claim
128 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: (a) polymerizing by melt condensation fumaric acid and propylene glycol at a temperature between about 100° C. and 140° C. for approximately 10 to 20 hours until polymers having a weight average molecular weight between 300 and 1000 and a number average molecular weight between 200 and 600 are formed; and (b) polymerizing by melt condensation the product step (a) at a temperature between greater than 140° C. to approximately 180° C. for about one to two hours until poly(propylene glycol fumarate) having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 is formed.
Claim 27
Independent Claim
128 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: (a) polymerizing by melt condensation fumaric acid and propylene glycol at a temperature between about 100° C. and 140° C. for approximately 10 to 20 hours until polymers having a weight average molecular weight between 300 and 1000 and a number average molecular weight between 200 and 600 are formed; and (b) polymerizing by melt condensation the product step (a) at a temperature between greater than 140° C. to approximately 180° C. for about one to two hours until poly(propylene glycol fumarate) having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 is formed.
Claim 28
Dependent Claim
28 words
The method of claim 19 wherein the closed system contains a trap to collect the water produced in the reaction between the fumaric acid and the propylene glycol.
Claim 29
Dependent Claim
23 words
The method of claim 19 wherein the reactants are fumaric acid and propylene glycol at a ratio of between about 1:1 and 1:1.1.
Claim 30
Independent Claim
74 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: polymerizing in a closed system mixture of fumaric acid and propylene glycol in the presence of an azeotrope to remove the water produced by the reaction until polymers having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 are produced.
Claim 31
Independent Claim
74 words
A method for producing poly(propylene glycol fumarate) having a controlled molecular weight, narrow polydispersity with minimal low molecular weight fractions, and high reproducibility comprising: polymerizing in a closed system mixture of fumaric acid and propylene glycol in the presence of an azeotrope to remove the water produced by the reaction until polymers having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 are produced.
Claim 32
Dependent Claim
37 words
The method of claim 22 wherein the azeotrope is xylene and the fumaric acid and propylene glycol are reacted in a closed system with a water collecting trap at reflux conditions for approximately 10 to 20 hours.
Claim 33
Independent Claim
66 words
A method for producing a biodegradable poly(propylene glycol fumarate) polymer having increased susceptibility to hydrolysis comprising polymerizing MPM and PFP trimers with a compound selected from the group consisting of lactic acid or glycolic acid to form copolymers having lactic acid linkages until polymers having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 are produced.
Claim 34
Independent Claim
66 words
A method for producing a biodegradable poly(propylene glycol fumarate) polymer having increased susceptibility to hydrolysis comprising polymerizing MPM and PFP trimers with a compound selected from the group consisting of lactic acid or glycolic acid to form copolymers having lactic acid linkages until polymers having weight average molecular weight of between 500 and 3000 and number average molecular weight between about 300 and 2000 are produced.
Claim 35
Dependent Claim
17 words
The method of claim 24 further comprising reacting the trimers at a ratio of MPM:PFP of 1:1.
Claim 36
Dependent Claim
16 words
The method of claim 24 further comprising reacting the trimers in the presence of a catalyst.
Claim 37
Dependent Claim
30 words
The method of claim 24 comprising reacting the trimers with a compound selected from the group consisting of lactic acid or glycolic acid to form copolymers having lactic acid linkages.
Claim 38
Independent Claim
53 words
A method for repairing damage to tissue or bone comprising applying a polymeric composition of fumaric acid and propylene glycol having a range of number average molecular weights between about 500 and 3000 and between 1 and 2 mmole carboxylic acid end groups per gram of polymer, and crosslinking the applied polymeric composition.
Claim 39
Independent Claim
53 words
A method for repairing damage to tissue or bone comprising applying a polymeric composition of fumaric acid and propylene glycol having a range of number average molecular weights between about 500 and 3000 and between 1 and 2 mmole carboxylic acid end groups per gram of polymer, and crosslinking the applied polymeric composition.
Claim 40
Dependent Claim
17 words
The method of claim 28 further comprising incorporating a radical source for crosslinking into the polymeric composition.
Claim 41
Independent Claim
64 words
A method for forming biocompatible, biodegradable implants comprising selecting a polymeric composition formed of fumaric acid and propylene glycol having a range of number average molecular weights between about 2000 and 100,000, dissolving the polymeric composition in a solvent at a concentration of between about 5 to 40% polymer in combination with a crosslinking agent, applying the solution and removing the solvent, and crosslinking.
Claim 42
Independent Claim
64 words
A method for forming biocompatible, biodegradable implants comprising selecting a polymeric composition formed of fumaric acid and propylene glycol having a range of number average molecular weights between about 2000 and 100,000, dissolving the polymeric composition in a solvent at a concentration of between about 5 to 40% polymer in combination with a crosslinking agent, applying the solution and removing the solvent, and crosslinking.
Claim 43
Dependent Claim
107 words
The polymeric composition of claim 1 for bone repair comprising: approximately 5 to 40% poly(propylene glycol fumarate); approximately 0 to 15% monomer selected from the group consisting of vinyl monomer, methacrylic acid, acrylic acid, alkyl esters of methacrylic acid, alkyl esters of acrylic acid, vinyl pyrrolidone, and vinyl acetate; approximately 45 to 90% filler selected from the group consisting of calcium slats, calcium carbonate, calcium sulfate, plaster of paris, hydroxy apatite, and bone; and a free radical initiator selected from the group consisting of benzoylperoxide, t-butyl hydroperoxide, methyl ethyl ketone peroxide, t-butyl perbenzoate, and an accelerator selected from the group consisting of N,N-dimethyl toludine and cobalt naphthanate.
Claim 44
Dependent Claim
29 words
The polymeric composition of claim 31 further comprising polymers of the poly(propylene glycol fumarate) and hydroxy acids selected from the group consisting of lactic acids, glycolic acid, and glycols.
Claim 45
Dependent Claim
12 words
The polymeric composition of claim 31 comprising approximately 45 to 90% filler.
Claim 46
Dependent Claim
9 words
The composition of claim 1 further comprising a drug.
Claim 47
Dependent Claim
14 words
The method of claim 30 further comprising adding a drug to the polymeric composition.
Claim 48
Dependent Claim
9 words
The composition of claim 31 further comprising a drug.
References Cited (Backward Citations)
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