DIMENSIONALLY STABLE, SHAPED ARTICLES COMPRISED OF DRIED, AGGREGATED, WATER-SWELLABLE HYDROGEL MICROSPHERES AND METHOD OF MAKING SAME

• US 20110009520A1
• Filed: 03/19/2009
• Published: 01/13/2011
• Est. Priority Date: 03/20/2008
• Status: Abandoned Application

• Current Assignee: Garret D. Figuly, Surbhi Mahajan
• Original Assignee: Garret D. Figuly, Surbhi Mahajan
• Inventors: Mahajan, Surbhi, Figuly, Garret D.
• Application Number:
  US12/919,558
• Publication Number:
  US 20110009520A1
• Time in Patent Office: Days
• US Class Current: 523/113
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids

Abstract

Dimensionally stable, shaped articles comprised of dried, aggregated, water-swellable hydrogel microspheres are described. The microspheres are aggregated together without the use of a binding agent. When exposed to an aqueous medium in a container, the dimensionally stable, shaped article swells slowly and disaggregates, forming at least partially swollen hydrogel microspheres, which take the shape of the container. The dimensionally stable, shaped articles disclosed herein have many potential applications, including medical applications such as a medical implant.

Claims

1. A dimensionally stable, shaped article comprising dried, water-swellable hydrogel microspheres, aggregated to form a predetermined shape, wherein said article does not contain a binding agent to bind the microspheres together.

2. The dimensionally stable, shaped article according to claim 1, wherein the water-swellable hydrogel microspheres comprise at least one monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacrylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, vinyl alcohol, vinyl acetate, methyl maleate, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, isobutylene, maleic anhydride, acrylonitrile, and ethylene glycol.

3. The dimensionally stable, shaped article according to claim 2, wherein the water-swellable hydrogel microspheres comprise acrylic acid and at least one monomer selected from the group consisting of sodium acrylate, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, styrene sulfonic acid, and the sodium salt of styrene sulfonic acid.

4. The dimensionally stable, shaped article according to claim 2, wherein the water-swellable hydrogel microspheres comprise styrene sulfonic acid or a combination comprising styrene sulfonic acid and the sodium salt of styrene sulfonic acid.

5. The dimensionally stable, shaped article according to claim 2, wherein the water-swellable hydrogel microspheres comprise acrylic acid, sodium acrylate and vinyl alcohol.

6. The dimensionally stable, shaped article according to claim 1, wherein said shaped article is a medical implant.

8. The dimensionally stable, shaped article according to claim 1, wherein the water-swellable hydrogel microspheres are made by a process comprising the steps of:

a) forming a first solution comprising;

(i) water;

(ii) at least one water miscible monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate;

provided that;

(A) if said at least one water miscible monomer is acrylamide, methacrylamide, N-substituted acrylamides, 2-hydroxyethyl acrylate, or 2-hydroxyethyl methacrylate, said monomer is used in combination with at least one other monomer selected from subgroup 1 consisting of;

acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid;

(B) if said first solution contains at least one water miscible monomer from subgroup 2 consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, but does not contain a monomer selected from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is at least about 3;

(C) if said first solution contains at least one water miscible monomer from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is less than about 3;

(iii) a crosslinking agent that is miscible in the first solution in less than or equal to about 5 Mol %, relative to total moles of monomer and crosslinking agent, said crosslinking agent being selected from the group consisting of N,N′

-methylene-bis-acrylamide, N,N′

-methylene-bis-methacrylamide, N-methylolacrylamide, N-methylolmethacrylamide, glycidyl acrylate, glycidyl methacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyvalent metal salts of acrylic acid and methacrylic acid, divinyl benzene phosphoacrylates, divinylbenzene, divinylphenylphosphine, divinyl sulfone, 1,3-divinyltetramethyldisiloxane, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5,5]undecane, phosphomethacrylates, ethylene glycol diglycidyl ether, glycerin triglycidyl ether, glycerin diglycidyl ether, and polyethylene glycol diglycidyl ether;

(iv) a water soluble protecting colloid;

(v) an emulsifier; and

(vi) a low temperature aqueous soluble azo initiator;

b) forming a second solution comprising at least one substantially chlorinated hydrocarbon of less than 6 carbon units, provided that the chlorinated hydrocarbon is not a halogenated aromatic hydrocarbon, and an organic soluble protecting colloid;

c) forming a first suspension with agitation comprising the first and second solutions at a temperature below the initiation temperature of the azo initiator of (a);

d) increasing the temperature of the agitating first suspension to a temperature at which the low temperature aqueous soluble azo initiator is activated;

e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;

f) allowing the second suspension to cool to a temperature that is at or below about 30°

C. while agitating the second suspension;

g) washing the second suspension at least once with a dehydrating solvent wherein water is removed from the microspheres forming a microsphere preparation; and

h) recovering the microsphere preparation.

9. The dimensionally stable, shaped article according to claim 8, wherein the second solution comprises a mixture of methylene chloride and chloroform.

10. The dimensionally stable, shaped article according to claim 8, wherein the azo initiator is 2,2′

-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride.

11. The dimensionally stable, shaped article according to claim 8, wherein the crosslinking agent is N,N′

-methylenebisacrylamide.

7. (canceled)

12. (canceled)

13. A method of making a dimensionally stable, shaped article comprised of dried, aggregated, water-swellable hydrogel microspheres comprising the steps of:

a) providing in a mold having a preselected shape, a suspension of water-swellable hydrogel microspheres in an aqueous medium wherein said microspheres are at least partially swollen; and

b) evaporatively drying said suspension to remove substantially all of the aqueous medium to form the dimensionally stable, shaped article;

wherein;

(i) said method is carried out in the absence of a binding agent; and

(ii) said dimensionally stable shaped article has the shape of the mold.

14. The method according to claim 13, wherein the water-swellable hydrogel microspheres comprise at least one monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacrylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, vinyl alcohol, vinyl acetate, methyl maleate, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, isobutylene, maleic anhydride, acrylonitrile, and ethylene glycol.

15. The method according to claim 14, wherein the water-swellable hydrogel microspheres comprise acrylic acid and at least one monomer selected from the group consisting of sodium acrylate, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, styrene sulfonic acid, and sulfonic acid sodium salt.

16. The method according to claim 14, wherein the water-swellable hydrogel microspheres comprise styrene sulfonic acid or a combination comprising styrene sulfonic acid and styrene sulfonic acid sodium salt.

17. The method according to claim 14, wherein the water-swellable hydrogel microspheres comprise acrylic acid, sodium acrylate and vinyl alcohol.

18. The method according to claim 13, wherein the dimensionally stable, shaped article is a medical implant.

19. The method according to claim 13, wherein the aqueous medium is water.

20. The method according to claim 13, wherein the evaporatively drying is done passively at ambient conditions of temperature and humidity.

21. The method according to claim 13, wherein the water-swellable hydrogel microspheres are made by a process comprising the steps of:

a) forming a first solution comprising;

(i) water;

(ii) at least one water miscible monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate;

provided that;

(A) if said at least one water miscible monomer is acrylamide, methacrylamide, N-substituted acrylamides, 2-hydroxyethyl acrylate, or 2-hydroxyethyl methacrylate, said monomer is used in combination with at least one other monomer selected from subgroup 1 consisting of;

acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid;

(B) if said first solution contains at least one water miscible monomer from subgroup 2 consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, but does not contain a monomer selected from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is at least about 3;

(C) if said first solution contains at least one water miscible monomer from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is less than about 3;

(iii) a crosslinking agent that is miscible in the first solution in less than or equal to about 5 Mol %, relative to total moles of monomer and crosslinking agent, said crosslinking agent being selected from the group consisting of N,N′

-methylene-bis-acrylamide, N,N′

-methylene-bis-methacrylamide, N-methylolacrylamide, N-methylolmethacrylamide, glycidyl acrylate, glycidyl methacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyvalent metal salts of acrylic acid and methacrylic acid, divinyl benzene phosphoacrylates, divinylbenzene, divinylphenylphosphine, divinyl sulfone, 1,3-divinyltetramethyldisiloxane, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5,5]undecane, phosphomethacrylates, ethylene glycol diglycidyl ether, glycerin triglycidyl ether, glycerin diglycidyl ether, and polyethylene glycol diglycidyl ether;

(iv) a water soluble protecting colloid;

(v) an emulsifier; and

(vi) a low temperature aqueous soluble azo initiator;

b) forming a second solution comprising at least one substantially chlorinated hydrocarbon of less than 6 carbon units, provided that the chlorinated hydrocarbon is not a halogenated aromatic hydrocarbon, and an organic soluble protecting colloid;

c) forming a first suspension with agitation comprising the first and second solutions at a temperature below the initiation temperature of the azo initiator of (a);

d) increasing the temperature of the agitating first suspension to a temperature at which the low temperature aqueous soluble azo initiator is activated;

e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;

f) allowing the second suspension to cool to a temperature that is at or below about 30°

C. while agitating the second suspension;

g) washing the second suspension at least once with a dehydrating solvent wherein water is removed from the microspheres forming a microsphere preparation; and

h) recovering the microsphere preparation.

22. (canceled)

23. (canceled)

24. (canceled)

25. A method for completely or partially blocking or filling a lumen or void within the body of a mammal comprising the steps of:

a) providing a dimensionally stable, shaped article comprised of dried, water-swellable hydrogel microspheres, aggregated to form a predetermined shape, wherein said article does not contain a binding agent to bind the microspheres together;

b) implanting the dimensionally stable, shaped article into a lumen or void within the body; and

c) allowing the dimensionally stable, shaped article to swell and disaggregate upon exposure to a physiological aqueous fluid present in or surrounding the lumen or void, thereby forming at least partially swollen hydrogel microspheres, which totally or partially block or fill the lumen or void.