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Claims for Patent: 4,757,128

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Claims for Patent: 4,757,128

Title: High molecular weight polyanhydride and preparation thereof
Abstract:High molecular weight polyanhydrides, defined as polyanhydrides having a molecular weight average greater than 20,000 or an intrinsic viscosity of greater than 0.3 dl/g in an organic solvent at room temperature, are formed by melt polycondensation of highly pure isolated prepolymers under optimized reaction conditions, particularly time and temperature with removal of the condensation product. Higher molecular weights are obtained by inclusion of a catalyst with the prepolymers in the melt polymerization. Catalysts used for transterification, ring opening polymerization and related polymerizations may be utilized. The high molecular weight polyanhydrides have improved physico-mechanical properties and are especially well suited for biomedical applications, particularly in controlled release devices for drug delivery.
Inventor(s): Domb; Abraham J. (Brookline, MA), Langer; Robert S. (Somerville, MA)
Assignee: Massachusetts Institute of Technology (Cambridge, MA)
Application Number:06/892,809
Patent Claims: 1. A high molecular weight polyanhydride having a weight average molecular weight of greater than 20,000 and an intrinsic viscosity of greater than 0.3 dl/g in chloroform at 23.degree. C., said polyanhydride produced from at least one dicarboxylic acid selected from the group consisting of:

aliphatic dicarboxylic acids having the formula:

aromatic dicarboxylic acids having the formula: ##STR7## aromatic dicarboxylic acids having the formula: ##STR8## aliphatic-aromatic dicarboxylic acids having the formula: ##STR9## aromatic and aliphatic heterocyclic dicarboxylic acids having the formula: ##STR10## wherein X is selected from the group consisting of oxygen, nitrogen, and sulfur, and

n is an integer between 1 and 3; and

aromatic and aliphatic heterocyclic dicarboxylic acids of the above formula in combination with at least one dicarboxylic acid selected from the group consisting of aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids having more than one phenyl group;

wherein the R groups are divalent organic radical groups.

2. A high molecular weight polyanhydride synthesized by:

polymerizing at least one highly pure prepolymer produced from a mixture of anhydrides prepared from at least one highly pure dicarboxylic acid at a temperature and for a reaction time to form a polyanhydride having a weight average molecular weight in excess of 20,000;

removing the polyanhydride condensation product having a weight average molecular weight in excess of 20,000 formed by said polymerization; and

stopping said polymerization before said polyanhydride condensation product decreases in molecular weight.

3. The high molecular weight polyanhydride of claim 2 wherein at least one dicarboxylic acid is selected from the group consisting of sebacic acid, 4,4'-[.alpha.,w-alkanediylbis(oxy)]bis[benzoic acid], isophthalic acid, dodecanedioic acid, 2,2'-[1,4-phenylenebis(oxy)]bisacetic acid, 1,4-bis(carboxymethyl)benzene, 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxy)]bisacetic acid, 2,2-bis(4-carboxyphenyl)propane; terephthalic acid; 1,4 phenylene dipropionic acid; 4,4'-(n-alkylidene)bis[benzoic acid]; and cyclohexane dicarboxylic acids.

4. The high molecular weight polyanhydride of claim 2 synthesized by polymerizing at least one highly pure prepolymer with a catalyst.

5. The high molecular weight polyanhydride of claim 4 wherein said catalyst is selected from the group of catalysts consisting of acid, base and coordination catalysts.

6. The high molecular weight polyanhydride of claim 5 wherein the catalyst is selected from the group consisting of (CH.sub.3 COO).sub.2 Cd, alkaline earth metal oxides, calcium carbonate and complexes of diethylzinc and hydroxylated compounds.

7. A composition comprising a high molecular weight polyanhydride synthesized by:

polymerizing at least one highly pure prepolymer produced from a mixture of anhydrides prepared from at least one highly pure dicarboxylic acid at a temperature and for a reaction time to form a polymer having a weight average molecular weight in excess of 20,000;

removing the polyanhydride condensation product having a weight average molecular weight in excess of 20,000 formed by said polymerization; and

stopping said polymerization before said polyanhydride condensation product decreases in molecular weight.

8. A composition comprising a high molecular weight polyanhydride having a weight average molecular weight of greater than 20,000 and an intrinsic viscosity of greater than 0.3 dl/g in chloroform at 23.degree. C., said polyanhydride produced from at least one dicarboxylic acid selected from the group consisting of:

aliphatic dicarboxylic acids having the formula:

aromatic dicarboxylic acids having the formula: ##STR11## aromatic dicarboxylic acids having the formula: ##STR12## aliphatic aromatic dicarboxylic acids having the formula: ##STR13## aromatic and aliphatic heterocyclic dicarboxylic acids having the formula: ##STR14## wherein X is selected from the group consisting of oxygen, nitrogen, and sulfur, and n is an integer between 1 and 3; and

aromatic and aliphatic heterocyclic dicarboxylic acids of the above formula in combination with at least one dicarboxylic acid selected from the group consisting of aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids having more than one phenyl group,

wherein R groups are divalent organic radical groups.

9. A high molecular weight polyanhydride having a weight average molecular weight of greater than 20,000 and an intrinsic viscosity of greater than 0.3 dl/g in chloroform at 23.degree. C., wherein said polyanhydride is produced from at least one dicarboxylic acid selected from the group consisting of sebacic acid, 4,4'-[.alpha.,w-alkanediylbis(oxy)]bis[benzoic acid], isophthalic acid, dodecanedioic acid, 2,2'-[1,4-phenylenebis(oxy)]bisacetic acid, 1,4-bis(carboxymethyl)benzene, 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxy)]bisacetic acid, 2,2-bis(4-carboxyphenyl)propane; terephthalic acid; 1,4 phenylene dipropionic acid; 4,4'-(n-alkylidene)bis[benzoic acid]; and cyclohexane dicarboxylic acids.

10. A method for synthesizing a high molecular weight polyanhydride comprising:

polymerizing at least one highly pure prepolymer prepared from at least one highly pure dicarboxylic acid at a temperature and for a reaction time to form a polyanhydride having a weight average molecular weight in excess of 20,000;

removing the polyanhydride condensation product having a weight average molecular weight in excess of 20,000 formed by said polymerization; and

stopping said polymerization before said polyanhydride condensation product decreases in molecular weight.

11. The method of claim 10 wherein the polymer is polymerized in the presence of a catalyst.

12. The method of claim 11 wherein the catalyst is selected from the group consisting of acid, base, and coordination catalysts.

13. The method of claim 12 wherein said catalyst is selected from the group consisting of (CH.sub.3 COO).sub.2 Cd, alkaline earth metal oxides, calcium carbonate, and complexes of diethylzinc and hydroxylated compounds.

14. The method of claim 10 further comprising forming at least one prepolymer from at least one highly pure dicarboxylic acid by refluxing said dicarboxylic acid in an aliphatic anhydride.

15. The method of claim 10 further comprising forming at least one prepolymer from at least one highly pure dicarboxylic acid by reacting said dicarboxylic acid with an aliphatic acid chloride in the presence of an organic base.

16. The method of claim 10 wherein said temperature is between 140.degree. C. and 250.degree. C. and said reaction time is between 10 minutes and 300 minutes.

17. The method of claim 10 wherein said polymerization is stopped before said polyanhydride forms an insoluble gel.

18. The method of claim 10 wherein said temperature is approximately 180.degree. C. and said reaction time is approximately 90 minutes.

19. The method of claim 10 further comprising selecting at least one dicarboxylic acid from the group consisting of:

aliphatic dicarboxylic acids having the formula:

aromatic dicarboxylic acids having the formula: ##STR15## aromatic dicarboxylic acids having the formula: ##STR16## aliphatic-aromatic dicarboxylic acids having the formula: ##STR17## aromatic and aliphatic heterocyclic dicarboxylic acids having the formula: ##STR18## wherein X is selected from the group consisting of oxygen, nitrogen, and sulfur, and n is an integer between 1 and 3; and

aromatic and aliphatic heterocyclic dicarboxylic acids of the above formula in combination with at least one dicarboxylic acid selected from the group consisting of aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids having more than one phenyl group,

wherein the R groups are divalent organic radical groups.

20. The method of claim 19 wherein at least one dicarboxylic acid is selected from the group consisting of:

sebacic acid, 4,4'-[.alpha.,w-alkanediylbis(oxy)]bis[benzoic acid], isophthalic acid, dodecanedioic acid, 2,2'-[1,4-phenylenebis(oxy)]bisacetic acid, 1,4-bis(carboxymethyl)benzene, 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxy)]bisacetic acid, 2,2-bis(4-carboxyphenyl)propane; terephthalic acid; 1,4 phenylene dipropionic acid; 4,4'-(n-alkylidene)bis[benzoic acid]; and cyclohexane dicarboxylic acids.
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