Hydrophilic or hydrogel carrier systems such as coatings, body implants and other articles

• US 3,975,350 A
• Filed: 06/25/1974
• Issued: 08/17/1976
• Est. Priority Date: 08/02/1972
• Status: Expired due to Term

• Current Assignee: HUDGIN, DONALD E., 33 BERKSHIRE DR., PRINCETON JUNCTION, NJ 08550
• Original Assignee: Princeton Polymer Laboratories, Inc.
• Inventors: Blair, Edgar Allan, Hudgin, Donald Edward
• Primary Examiner(s): Cockeram, H.S.
• Application Number:
  US05/482,874
• Time in Patent Office: 784 Days
• Field of Search: 260/2.5 AD, 260/75 NK, 260/77.5 AP, 260/2.5 A, 260/30.4 N, 260/32.6 N, 260/77.5 AQ, 239/6, 239/57, 3/1, 3/1.4, 424/78
• US Class Current: 524/108
• CPC Class Codes: A01N 25/10 Macromolecular compounds
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 8/042 Gels
• CPC Class Codes: A61K 8/87 Polyurethanes
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61Q 3/02 Nail coatings
• CPC Class Codes: A61Q 5/06 Preparations for styling the hair, e.g. by temporary shaping or colouring
• CPC Class Codes: B01D 71/54 Polyureas; Polyurethanes
• CPC Class Codes: C08G 18/0804 Manufacture of polymers containing ionic or ionogenic groups
• CPC Class Codes: C08G 18/42 Polycondensates having carboxylic or carbonic ester groups in the main chain
• CPC Class Codes: C08G 18/48 Polyethers
• CPC Class Codes: C08G 18/50 having heteroatoms other than oxygen
• CPC Class Codes: C08G 18/52 Polythioethers
• CPC Class Codes: C08G 18/60 Polyamides or polyester-amides
• CPC Class Codes: C08G 18/62 Polymers of compounds having carbon-to-carbon double bonds
• CPC Class Codes: C08G 18/6423 Polyalkylene polyamines; polyethylenimines; Derivatives thereof polyamides or polyesteramides C08G18/60
• CPC Class Codes: C08G 18/6453 having sulfur
• CPC Class Codes: C08G 18/6461 having phosphorus
• CPC Class Codes: C08G 18/68 : Unsaturated polyesters
• CPC Class Codes: C08G 2210/00 : Compositions for preparing hydrogels
• CPC Class Codes: Y10S 521/905 : Hydrophilic or hydrophobic cellular product

Abstract

Improved active agent systems with novel carriers as membrane, release, and coating polymers for said active agents; the polymers are water absorptive polyurethane polymers prepared from resins having a low ratio of carbon to oxygen to nitrogen or having ionic, quaternary ammonium or salt groups in the resin backbone and a low amount of isocyanate; the water absorptivity of the polyurethane polymers is above 10%, preferably above 20%, and these polymers may range to completely gel-like, high water absorbtive polymers; these active agent polymers are useful as in medicinal, insecticidal, pesticidal, algaecidal, etc. applications; as well as zero release agents, body implants and coatings requiring hydrophilic properties; other use for the active agent systems are in sensing membranes or coatings or ion transport recognition devices such as in gaseous or liquid media; as a hydrogel providing a leachable matrix wherein the leaching agent may be body fluids, e. g., animals or human, e. g., productive livestock and domestic animals and/or pets, or animals used in medicinal or veterinary research, e. g., monkeys, mice, dogs, hamsters, rabbits, guinea pigs, cats, etc.

Claims

1. A carrier system comprising an active agent and a hydrophilic polymer as a carrier vehicle therefor, said carrier vehicle comprising a crosslinked polyurethane polymer consisting essentially of

A. as a resin precursor of said polyurethane polymer, a polyfunctional resin having an equivalent weight of more than 170 and up to 2000 and a numerical carbon to oxygen or carbon to nitrogen ratio of up to 2.5:

1 to 1.2;

1 or a numerical carbon to ionic group ratio in said resin of 20;

1 to 6;

1, said resin being selected from the class consisting of;

1. an adduct of

a. a dihydroxy compound with propylene imine, ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

b. a trihydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

c. a tetrahydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

d. a polyhydroxy compound of more than 4--OH groups with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

e. a hydroxy carboxylic acid or a sugar acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

f. low molecular weight, hydrolyzed polyvinyl acetate, polyacrylic acid or polymethacrylic acid with ethylene oxide, ethylene imine, dioxolane or mixtures of same;

2.

3. said isocyanate to said resin. 2. The carrier system for an active agent as defined in claim 1 and wherein the crosslinked polyurethane polymer is as defined in claim 1 and wherein the resin is a resin having a carbon to oxygen or amine ratio of 2.5 to 1 to 1.2 to 1 of an equivalent weight of more than 170 and a molecular weight less than 2000.

4. The carrier system for an active agent as defined in claim 1 and wherein the crosslinked polyurethane polymer is as defined in claim 1 and wherein the isocyanate is in an amount from 0.02 to 0.15 in excess of the equimolar ratio in reference to the equimolar amount of said isocyanate.

5. The carrier system for an active agent as defined in claim 1 and wherein the crosslinked polyurethane polymer is as defined in claim 1 and wherein the isocyanante to resin is in an amount from 0.02 to 0.10 in excess of the equimolar ratio in reference to the equimolar amount of said isocyanate to said resin.

6. The carrier system for an active agent as defined in claim 1 and wherein the crosslinked polyurethane polymer as defined in claim 1 and wherein the defined excess ratio of isocyanate to resin is 0.02 to 0.1.

7. The carrier system defined in claim 1 and wherein the same is zero order release system.

8. The carrier system as defined in claim 1 and wherein the same is a leachable carrier system.

9. The carrier system as defined in claim 7 wherein the leachable carrier system is an aqueous medium leachable carrier system.

10. The carrier system as defined in claim 7 and wherein the leachable carrier system is a body fluid leachable carrier system.

11. The carrier system as defined in claim 1 wherein the same is a release system for releasing said active agent in a gaseous medium.

12. The carrier system as defined in claim 10 wherein the gaseous medium is air.

13. The carrier system as defined in claim 1 and wherein the polyurethane polymer contains a reaction site for said active agent.

14. The carrier system as defined in claim 1 and wherein the polyurethane polymer as carrier for said active agent is disposed in a liquid medium.

15. The carrier system as defined in claim 13 and wherein the liquid medium is a body fluid.

16. The carrier system as defined in claim 1 and wherein the polyurethane polymer contains reaction sites disposed in a gaseous medium.

17. The carrier system as defined in claim 15 and wherein the gaseous medium is air.

25. The carrier system as defined in claim 1 and wherein the polyurethane polymer is a solution of polymer in dimethylformamide, dioxane or butyrolactone.

26. In a method for releasing an active agent in a medium in which said active agent is used improvement comprising:

incorporating said active agent in a polyurethane polymer as defined in claim 1;

exposing said polyurethane with said active agent to said medium; and

releasing said active agent into said medium at a predetermined rate.

27. The carrier system as defined in claim 1 and wherein the active agent is a therapeutically or biologically active agent.

28. The coating as defined in claim 17 and wherein the same is applied in its noncrosslinked state and curing is effected subsequently.

2. an adduct of trimellitic acid, orthophosphoric acid, pyromellitic acid, or mellitic acid with ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

3. an adduct of pyrophosphoric acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

4. an adduct of ammonia or a polyamino compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

5. an ammonium or quaternary ammonium salt of said adduct of ammonia or a polyamino compound;

6. a sulfonated reactive-H group terminated polyester resin of a maleic acid ester, itaconic acid ester, fumaric acid ester, mesoconic acid ester or citraconic acid ester wherein a dihydroxy compound precursor of said ester is a glycol of 2 to 6 carbon atoms;

7. a reactive-H group terminated polyester amide of a lower alkyl dialkanol amine and a diacid wherein said acid is adipic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, fumaric acid, itaconic acid, mesoconic acid, citraconic acid, and an ammonium or quaternary ammonium compound of said amine groups;

8. a reactive-H group terminated linear of slightly branched polyamide wherein the amine precursor of said amide is diethylene triamine, triethylene tetramine, tetraethylene pentamine, a polyloweralkylene imine, and the acid precursor of said amide is adipic, sebacic, maleic, azelaic, phthalic, itaconic, mesoconic, or citraconic, an amine salt or mixtures of same, a hydrammonium quaternary ammonium compound thereof, or an adduct of said amide with ethylene oxide, ethylene glycol, dioxolane or propylene glycol;

9. a reactive-H group terminated polysulfhydryl resin having in the backbone thereof sulfonium, sulfoxide, or sulfone groups; and

10. mixtures of above resins;

B. as a urethane linkage precursor of said polyurethane polymer, an aliphatic, alicyclic-aliphatic, mixed aliphatic-aromatic or an aromatic polyfunctional isocyanate, a nitrile carbonate or mixtures of same of a functionality of 2 or higher in an amount from 0.02 in excess of one equivalent weight of isocyanante times its functionality per equivalent weight of resin times its functionality up to equi-equivalent weight of

18. A water absorbent coating comprising a crosslinked polyurethane polymer consisting essentially of

A. as a resin precursor of said polyurethane polymer, a polyfunctional resin having an equivalent weight of more than 170 and up to 2000 and a numerical carbon to oxygen or carbon to nitrogen ratio of up to 2.5:

1 to 1.2;

1 or a numerical carbon to ionic group ratio in said resin of 20;

1 to 6;

1, said resin being selected from the class consisting of;

1. an adduct of

a. a dihydroxy compound with propylene imine, ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

b. a trihydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

c. a tetrahydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

d. a polyhydroxy compound of more than 4--OH groups with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

e. a hydroxy carboxylic acid or a sugar acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

f. low molecular weight, hydrolyzed polyvinyl acetate, polyacrylic acid or polymethacrylic acid with ethylene oxide, ethylene imine, dioxolane or mixtures of same;

2. an adduct of trimellitic acid, orthophosphoric acid, pyromellitic acid, or mellitic acid with ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

3. an adduct of pyrophosphoric acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

4. an adduct of ammonia or a polyamino compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

5. an ammonium or quaternary ammonium salt of said adduct of ammonia or a polyamino compound;

6. a sulfonated reactive-H group terminated polyester resin of a maleic acid ester, itaconic acid ester, fumaric acid ester, mesoconic acid ester or citraconic acid ester wherein a dihydroxy compound precursor of said ester is a glycol of 2 to 6 carbon atoms;

7. a reactive-H group terminated polyester amide of a lower alkyl dialkanol amine and a diacid wherein said acid is adipic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, fumaric acid, itaconic acid, mesoconic acid, citraconic acid, and an ammonium or quaternary ammonium compound of said amine groups;

8. a reactive-H group terminated linear of slightly branched polyamide wherein the amine precursor of said amide is diethylene diamine, triethylene tetramine, tetraethylene pentamine, a polyloweralkylene imine, and the acid precursor of said amide is adipic, sebacic, maleic azelaic, phthalic, itaconic, mesoconic, or citraconic, an amine salt or mixtures of same, a hydroammonium quaternary ammonium compound thereof, or an adduct of said amide with ethylene oxide, ethylene glycol, dioxolane or propylene glycol;

9. a reactive--H group terminated polysulfhydryl resin having in the backbone thereof sulfonium, sulfoxide, or sulfone groups; and

10. mixtures of above resins;

B. as a urethane linkage precursor of said polyurethane polymer, an aliphatic, alicyclic-aliphatic, mixed aliphatic-aromatic or an aromatic polyfunctional isocyanate, a nitrile carbonate or mixtures of same of a functionality of 2 or higher in an amount from 0.02 in excess of one equivalent weight of isocyanate times its functionality per equivalent weight of resin times its functionality up to equi-equivalent weight of said isocyanate to said resin.

19. A body implant comprising a crosslinked polyurethane polymer consisting essentially of

A. as a resin precursor of said polyurethane polymer, a polyfunctional resin having an equivalent weight of more than 170 and up to 2000 and a numerical carbon to oxygen or carbon to nitrogen ratio of up to 2.5:

1 to 1.2;

1 or a numerical carbon to ionic group ratio in said resin of 20;

1 to 6;

1, said resin being selected from the class consisting of;

1. an adduct of

a. a dihydroxy compound with propylene imine, ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

b. a trihydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

c. a tetrahydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

d. a polyhydroxy compound of more than 4--OH groups with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

e. a hydroxy carboxylic acid or a sugar acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

f. low molecular weight, hydrolyzed polyvinyl acetate, polyacrylic acid or polymethacrylic acid with ethylene oxide, ethylene imine, dioxolane or mixtures of same;

20. an adduct of trimellitic acid, orthosphoric acid, pyromellitic acid, or mellitic acid with ethylene oxide, propylene oxide,, ethylene imine, dioxolane or mixtures of same;

3. an adduct of pyrophosphoric acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

4. an adduct of ammonia or a polyamino compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane, or mixtures of same;

5. an ammonium or quaternary ammonium salt of said adduct of ammonia or a polyamino compound;

6. a sulfonated reactive-H group terminated polyester resin of a maleic acid ester, itaconic acid ester, fumaric acid ester, mesoconic acid ester or citraconic acid ester wherein a dihydroxy compound precursor of said ester is a glycol of 2 to 6 carbon atoms;

21. a reactive-H group terminated polyester amide of a lower alkyl dialkanol amine and a diacid wherein said acid is adipic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, fumaric acid, itaconic acid, mesoconic acid, citraconic acid, and an ammonium or quaternary ammonium compound of said amine groups;

8. a reactive-H group terminated linear of slightly branched polyamide wherein the amine precursor of said amide is diethylene triamine, thriethylene tetramine, tetraethylene pentamine, a polyloweralkylene imine, and the acid precursor of said amide is adipic, sebacic, maleic azelaic, phthalic, itaconic, mesoconic, or citraconic, an amine salt or mixtures of same, a hydrammonium quaternary ammonium compound thereof or an adduct of said amide with ethylene oxide, ethylene glycol, dioxolane or propylene glycol;

9. a reactive-H group terminated polysulfhydryl resin having in the backbone thereof sulfonium, sulfoxide, or sulfone groups; and

10. mixtures of above resins;

B. as a urethane linkage precursor of said polyurethane polymer, and aliphatic, alicyclic-aliphatic, mixed aliphatic-aromatic or an aromatic polyfunctional isocyanate, a nitrile carbonate or mixtures of same of a functionality of 2 or higher in an amount from 0.02 in excess of one equivalent weight of isocyanate times its functionality per equivalent weight of resin times its functionality up to equi-equivalent weight of said isocyanate to said resin.

22. A wet friction elastomer comprising a crosslinked polyurethane polymer consisting essentially of

A. as a resin precursor of said polyurethane polymer, a polyfunctional resin having an equivalent weight of more than 170 and up to 2000 and a numerical carbon to oxygen or carbon to nitrogen ratio of up to 2.5:

1 to 1.2;

1 or a numerical carbon to ionic group ratio is said resin of 20;

1 to 6;

1, said resin being selected from the class consisting of;

23. an adduct of

a. a dihydroxy compound with propylene imine, ethylene oxide, propylene oxide, ethylene imine, dioxolane or mixtures of same;

b. a trihydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

c. a tetrahydroxy compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

d. a polyhydroxy compound of more than 4--OH groups with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

e. a hydroxy carboxylic acid or a sugar acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

f. low molecular weight, hydrolyzed polyvinyl acetate, polyacrylic acid or polymethacrylic acid with ethylene oxide, ethylene imine, dioxolane or mixtures of same;

2. an adduct of trimellitic acid, orthophosphoric acid, pyromellitic acid, or mellitic acid with ethylene oxide, propylene oxide, ethylene imine, dioxalane or mixtures of same;

3. an adduct of pyrophosphoric acid with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

24. an adduct of ammonia or a polyamino compound with ethylene oxide, propylene oxide, ethylene imine, propylene imine, dioxolane or mixtures of same;

5. an ammonium or quaternary ammonium salt of said adduct of ammonia or a polyamino compound;

6. a sulfonated reactive--H group terminated polyester resin of a maleic acid ester, itaconic acid ester, fumaric acid ester, mesoconic acid ester or citraconic acid ester wherein a dihydroxy compound precursor of said ester is a glycol of 2 to 6 carbon atoms;

7. a reactive--H group terminated polyester amide of a lower alkyl dialkanol amine and a diacid wherein said acid is adipic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, fumaric acid, itaconic acid, mesoconic acid, citraconic acid, and an ammonium or quaternary ammonium compound of said amine groups;

8. a reactive--H group terminated linear of slightly branched polyamide wherein the amine precursor of said amide is diethylene triamine, triethylene tetramine, tetraethylene pentamine, a polyloweralkylene imine, and the acid precursor of said amide is adipic, sebacic, maleic azelaic, phthalic, itaconic, mesoconic, or citraconic, an amine salt or mixtures of same, a hydrammonium quaternary ammonium compound thereof, or an adduct of said amide with ethylene oxide, ethylene glycol, dioxolane or propylene glycol;

9. a reactive--H group terminated polysulfhydryl resin having in the backbone thereof sulfonium, sulfoxide, or sulfone groups; and

10. mixtures of above resins;

B. as a urethane linkage precursor of said polyurethane polymer, an aliphatic, alicyclic-aliphatic, mixed aliphatic-aromatic or an aromatic polyfunctional isocyanate, a nitrile carbonate or mixtures of same of a functionality of 2 or higher in an amount from 0.05 in excess of one equivalent weight of isocyanate times its functionality per equivalent weight of resin times its functionality up to equi-equivalent weight of said isocyanate to said resin.