Temperature controlled and pH dependent self gelling biopolymeric aqueous solution

• US 8,920,842 B2
• Filed: 10/09/2009
• Issued: 12/30/2014
• Est. Priority Date: 11/15/1999
• Status: Expired due to Fees

• Current Assignee: Smith & Nephew Orthopaedics Ag (Smith & Nephew PLC)
• Original Assignee: Piramal Healthcare Limited (Piramal Enterprises Limited)
• Inventors: Chenite, Abdellatif, Selmani, Amine, Chaput, Cyril, Wang, Dong
• Primary Examiner(s): Fubara, Blessing M
• Application Number:
  US12/576,354
• Publication Number:
  US 20100028434A1
• Time in Patent Office: 1,908 Days
• Field of Search: 424/484, 424/485, 424/93.7, 424/93.1, 424/488, 514/777, 514/774
• US Class Current: 424/488
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/22 Polypeptides or derivatives thereof , e.g. degradation products
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The present invention relates a biopolymeric liquid aqueous composition for producing self-gelling systems and gels, which comprises: an acidic water-based medium, 0.1 to 10% by weight of a pH-gelling acid-soluble biopolymer; and 0.1 to 10% by weight of a water-soluble molecule having a basic character and a pKa between 6.0 and 8.4, or a water-soluble residue or sequence of the molecule having a basic character and a pKa between 6.0 and 8.4. The liquid composition has a final pH ranging from 5.8 and 7.4, and forms a stable solid and homogeneous gel within a temperature range from 10 to 70° C. The present invention also relates to a method for preparing the composition and uses thereof.

Claims

1. A polymeric self-gelling composition that remains liquid at temperature between 4°

C. and 15°

C. and solidifies when heated between 30°

C. and 60°

C., said self-gelling composition comprising;

a) an acidic water-based medium at a temperature between 4°

C. and 15°

C.;

b) 0.1 to 10% by weight of a pH-gelling acid-soluble polymer, with the proviso that said polymer is free of chitosan, and wherein said polymer is collagen; and

c) 0.1 to 10% by weight of a water-soluble molecule having a pKa between 6.0 and 8.4;

wherein said self-gelling composition has a final pH ranging from 5.8 and 7.4, and forms a stable solid and homogeneous gel when heated to temperature of 30°

C.-60°

C.

2. The composition according to claim 1, wherein said composition is prepared from organic and/or inorganic acid.

3. The composition according to claim 2, wherein the organic and/or inorganic acid is selected from the group consisting of hydrochloric acid, citric acid, ascorbic acid, lactic acid, lactobionic acid, acetic acid, salicylic acid, formic acid, glutamic acid, phosphoric acid, orthophosphoric acid, and glycerophosphoric acid, or a mixture thereof.

4. The composition according to claim 1, wherein said water-soluble molecule is an organic salt selected from the group consisting of mono-phosphate salt, mono-sulfonate salt, mono-sulfate salt and mono-carboxylate salt.

5. The composition according to claim 1, wherein said water-soluble molecule is a salt of polyol selected from the group consisting of mono-phosphate dibasic salt, mono-sulfonate salt, mono-sulfate salt and mono-carboxylate salt of polyol, said polyol being selected from the group consisting of glycerol, histidinol, acetol, diethylstil-bestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol, palmitoyl-glycerol, linoleoyl-glycerol, oleoyl-glycerol, and arachidonoyl-glycerol, or a mixture thereof.

6. The composition according to claim 5, wherein the salt of glycerol is selected from the group consisting of glycerol-2-phosphate, sn-glycerol 3-phosphate and L-glycerol-3-phosphate salt, or a mixture thereof.

7. The composition according to claim 1, wherein said water-soluble molecule is a salt of a sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfonate salt, mono-sulfate salt and mono-carboxylate salt of a sugar, said sugar being selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, and methylthio-deoxy-ribulose, or a mixture thereof.

8. The composition according to claim 1, wherein said water-soluble molecule is selected from the group consisting of sodium, magnesium or iron salt of glycerol-2-phosphate, sn-glycerol-3-phosphate and L-glycerol-3-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate and fructose-6-phosphate, or a mixture thereof.

9. The composition according to claim 1, wherein said water-soluble molecule is selected from the group consisting of N-[carbamoylmethyl]-2-aminoethane sulfonate (ACES), N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonate (BES), 3-[N,N-bis(2-hydroxy-ethyl)amino]-2-hydroxypropanesulfonate (DIPSO), N-[2-hydroxyethyl]piperazine-N′

-3-propane-sulfonate (EPPS), N-[2-hydroxyethyl]piperazine-N′

-4-butane-sulfonate (HEPBS), N-[2-hydroxyethyl]piperazine-N′

-2-ethanesulfonate (HEPES), N-[2-hydroxyethyl]piperazine-N′

-2-hydroxypropanesulfonate (HEPSO), 2-[N-morpholino]ethanesulfonate (MES), 4-[N-morpholino]butanesulfonate (MOBS), 3-[N-morpholino]propanesulfonate (MOPS), 3-[N-morpholino]-2-hydroxypropanesulfonate (MOPSO), Piperazine-N,N′

-bis[2-ethanesulfonate] (PIPES), Piperazine-N,N′

-bis[2-hydroxypropanesulfonate] (POPSO), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonate (TAPSO), and N-tris[hydroxymethyl]methyl-2-aminoethanesulfonate (TES), and mixtures thereof.

10. The composition according to claim 1, wherein said water-soluble molecule is selected from the group consisting of N,N-bis[hydroxyethyl]glycine (BICINE), bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BIS-TRIS), Glycyl-glycine (GLY-GLY), Triethanolamine (TEA), N-tris[hydroxymethyl]methylglycine (TRICINE), and Tris[hydroxymethyl]aminomethane (TRIZMA), and mixtures thereof.

11. The composition according to claim 1, wherein said water-soluble molecule has either one acid group and at least one amino group, or more amino groups than acid groups.

12. The composition according to claim 1, wherein said water-soluble molecule is an amino-acid residue, or a poly(amino acids) having a pKa between 6.0 and 8.4.

13. The composition according to claim 12, wherein said amino acid residue is selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), asparagine (ASN), and glutamine (GLN), or a mixture thereof.

14. The composition according to claim 1, wherein said water-soluble molecule is an amino acid residue selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), and glutamine (GLN), said amino acid residue or amino acid derivative being modified with a radical acetyl, t-butyl, benzyl, benzoyl, ethyl, formyl, or methyl.

15. The composition according to claim 1, wherein said water-soluble molecule is a polymer of at least one amino acid selected from the group consisting of alanine (ALA), histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), glutamine (GLN), glycine (GLY), hydroxyproline (HYP), isoleucine (ILE), leucine (LEU), norleucine (NLE), phenylalanine (PHE), proline (PRO), serine (SER), threonine (THR), tyrosine (TYR), and valine (VAL).

16. The composition according to claim 1, wherein said composition further comprises at least one other water-soluble polymer.

17. The composition according to claim 16, wherein said at least one other water-soluble polymer is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propyl cellulose, polyethylene oxide, polypropylene oxide, poly(ethylene oxide-co-propylene oxide) copolymers, poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) copolymers, polyvinyl alcohol, and polycaprolactone diols, and mixtures thereof.

18. The composition according to claim 1, further comprising a solid particulate or a water-soluble additive.

19. The composition according to claim 1, further comprising a drug or a pharmaceutical agent.

20. The composition according to claim 1, further comprising microorganisms, plant cells, animal cells or human cells dispersed therein.

21. The composition according to claim 1, for use as a carrier for delivering a pharmaceutical agent in situ.

22. The composition of claim 1, wherein said composition is loaded with cells selected from the group consisting of chondrocytes (articular cartilage), fibrochondrocytes (meniscus), ligament fibroblasts (ligament), skin fibroblasts (skin), tenocytes (tendons), myofibroblasts (muscle), mesenchymal stem cells and keratinocytes (skin).

23. A method for preparing a composition according to claim 1, which comprises the steps of:

a) dissolving a pH-gelling acid-soluble polymer within an aqueous acidic solution of a pH from about 1.0 to about 5.0 at temperature between 4°

C. and 15°

C. to obtain an aqueous polymer composition having a concentration of 0.1 to 10% by weight of said polymer, said polymer being free of chitosan, wherein said polymer is collagen;

b) dissolving 0.1 to 10% by weight of a water-soluble molecule having a pKa between 6.0 and 8.4 within said aqueous polymer composition to obtain a clear liquid formulation with a pH ranging between 5.8 and 7.4 at temperature between 4°

C. and 15°

C.;

c) heating said liquid formulation at a temperature between 30°

C. and 60°

C. to obtain a solid gel, said gel having a pH from about 5.8 to about 7.4.

24. The method of claim 23, wherein said aqueous acidic solution is prepared from an organic or inorganic acid selected from the group consisting of acetic acid, ascorbic acid, glutamic acid, lactic acid, lactobionic acid, salicylic acid, phosphoric acid, hydrochloric acid, propionic acid, and formic acid, or a mixture thereof.

25. The method of claim 23, wherein said water-soluble molecule is an organic salt selected from the group consisting of a mono-phosphate salt, a mono-sulfonate salt, a mono-sulfate salt and a mono-carboxylate salt.

26. The method of claim 23, wherein said water-soluble molecule is a salt of polyol selected from the group consisting of a mono-phosphate dibasic salt, a mono-sulfonate salt, a mono-sulfate salt and a mono-carboxylate salt of polyol, said polyol being selected from the group consisting of glycerol, histidinol, acetol, diethylstil-bestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol, palmitoyl-glycerol, linoleoyl-glycerol, oleoyl-glycerol, and arachidonoyl-glycerol, or a mixture thereof.

27. The method of claim 26, wherein said salt of glycerol is selected from the group consisting of glycerol-2-phosphate, sn-glycerol 3-phosphate and L-glycerol-3-phosphate salts, or a mixture thereof.

28. The method of claim 23, wherein said water-soluble molecule is a salt of sugar selected from the group selected from a mono-phosphate dibasic salt, a mono-sulfonate salt, a mono-sulfate salt and a mono-carboxylate salt of sugar, said sugar being selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, and methylthio-deoxy-ribulose, or a mixture thereof.

29. The method of claim 23, wherein said water-soluble molecule is a sodium, magnesium or iron salt of glycerol-2-phosphate, sn-glycerol-3-phosphate and L-glycerol-3-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate or fructose-6-phosphate, or a mixture thereof.

30. The method of claim 23, wherein said water-soluble molecule is selected from the group consisting of N-[carbamoylmethyl]-2-aminoethane sulfonate (ACES), N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonate (BES), 3-[N,N-bis(2-hydroxy-ethyl)amino]-2-hydroxypropanesulfonate (DIPSO), N-[2-hydroxyethyl]piperazine-N′

-3-propane-sulfonate (EPPS), N-[2-hydroxyethyl]piperazine-N′

-4-butane-sulfonate (HEPBS), N-[2-hydroxyethyl]piperazine-N′

-2-ethanesulfonate (HEPES), N-[2-hydroxyethyl]piperazine-N′

-2-hydroxypropanesulfonate (HEPSO), 2-[N-morpholino]ethanesulfonate (MES), 4-[N-morpholino]butanesulfonate (MOBS), 3-[N-morpholino]propanesulfonate (MOPS), 3-[N-morpholino]-2-hydroxypropanesulfonate (MOPSO), Piperazine-N,N′

-bis[2-ethanesulfonate] (PIPES), Piperazine-N,N′

-bis[2-hydroxypropanesulfonate] (POPSO), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonate (TAPSO), and N-tris[hydroxymethyl]methyl-2-aminoethanesulfonate (TES), and mixtures thereof.

31. The method of claim 23, wherein said water-soluble molecule is selected from the group consisting of N,N-bis[hydroxyethyl]glycine (BICINE), bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BIS-TRIS), Glycyl-glycine (GLY-GLY), Triethanolamine (TEA), N-tris[hydroxymethyl]methylglycine (TRICINE), and Tris[hydroxymethyl]aminomethane (TRIZMA), and mixtures thereof.

32. The method of claim 23, wherein said water-soluble molecule has either one acid group and at least one amino group, or more amino groups than acid groups.

33. The method of claim 23, wherein said water-soluble molecule is an amino-acid residue or a poly(amino acids) having a pKa between 6.0 and 8.4.

34. The method of claim 33, wherein said amino acid residue is selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), asparagine (ASN), glutamine (GLN), or a mixture thereof.

35. The method of claim 33, wherein said water-soluble molecule is an amino acid residue selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), and glutamine (GLN) modified with a radical acetyl, t-butyl, benzyl, benzoyl, ethyl, formyl, or methyl.

36. The method of claim 23, wherein said water-soluble molecule is a polymer of at least one amino acid selected from the group consisting of alanine (ALA), histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), glutamine (GLN), glycine (GLY), hyroxyproline (HYP), isoleucine (ILE), leucine (LEU), norleucine (NLE), phenylalanine (PHE), proline (PRO), serine (SER), threonine (THR), tyrosine (TYR), and valine (VAL).

37. The method of claim 23, wherein said aqueous polymer composition turns into a gel at a temperature above 37°

C.

38. The method of claim 23, wherein said polymer solution further comprises a solid particulate additive, said solid particulate additive being added to the polymer solution of step a) or b).

39. The method of claim 23, further comprising another water-soluble polymer added to the polymer solution of step a) or b), said other water-soluble polymer being free of chitosan.

40. The method of claim 39, wherein said other polymer is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propyl cellulose, polyethylene oxide, polypropylene oxide, poly(ethylene oxide-co-propylene oxide) copolymers, poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) copolymers, polyvinyl alcohol, and polycaprolactone diols.

41. A polymeric liquid aqueous composition for producing self-gelling systems and gels at temperature between 30°

C. and 60°

C., which comprises;

a) an acidic water-based medium at a temperature between 4°

C. and 15°

C.; and

b) 0.1 to 10% by weight of a pH-gelling acid-soluble polymer, wherein said polymer is collagen; and

c) 0.1 to 10% by weight of a water-soluble molecule having a pKa between 6.0 and 8.4, said water-soluble molecule being free of salt of polyol and sugar;

wherein said liquid composition has a final pH ranging from 5.8 and 7.4, and forms a stable solid and homogeneous gel when heated within a temperature range between 30°

C. and 60°

C.

42. The composition according to claim 41, wherein said composition is prepared from organic and/or inorganic acid.

43. The composition according to claim 42, wherein the organic and/or inorganic acid is selected from the group consisting of hydrochloric acid, citric acid, ascorbic acid, lactic acid, lactobionic acid, acetic acid, salicylic acid, formic acid, glutamic acid, phosphoric acid, orthophosphoric acid, and glycerophosphoric acid, or a mixture thereof.

44. The composition according to claim 41, wherein said polymer comprises a pH-gelling acid-soluble polysaccharide, polypeptidic or poly(amino acids), or synthetic polymer.

45. The composition according to claim 41, wherein said water-soluble molecule is an organic salt selected from the group consisting of mono-phosphate salt, mono-sulfonate salt, mono-sulfate salt and mono-carboxylate salt.

46. The composition according to claim 41, wherein said water-soluble molecule is selected from the group consisting of N-[carbamoylmethyl]-2-aminoethane sulfonate (ACES), N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonate (BES), 3-[N,N-bis(2-hydroxy-ethyl)amino]-2-hydroxypropanesulfonate (DIPSO), N-[2-hydroxyethyl]piperazine-N′

-3-propane-sulfonate (EPPS), N-[2-hydroxyethyl]piperazine-N′

-4-butane-sulfonate (HEPBS), N-[2-hydroxyethyl]piperazine-N′

-2-ethanesulfonate (HEPES), N-[2-hydroxyethyl]piperazine-N′

-2-hydroxypropanesulfonate (HEPSO), 2-[N-morpholino]ethanesulfonate (MES), 4-[N-morpholino]butanesulfonate (MOBS), 3-[N-morpholino]propanesulfonate (MOPS), 3-[N-morpholino]-2-hydroxypropanesulfonate (MOPSO), Piperazine-N,N′

-bis[2-ethanesulfonate] (PIPES), Piperazine-N,N′

-bis[2-hydroxypropanesulfonate] (POPSO), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonate (TAPSO), and N-tris[hydroxymethyl]methyl-2-aminoethanesulfonate (TES), and mixtures thereof.

47. The composition according to claim 41, wherein said water-soluble molecule is selected from the group consisting of N,N-bis[hydroxyethyl]glycine (BICINE), bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BIS-TRIS), Glycyl-glycine (GLY-GLY), Triethanolamine (TEA), N-tris[hydroxymethyl]methylglycine (TRICINE), and Tris[hydroxymethyl]aminomethane (TRIZMA), and mixtures thereof.

48. The composition according to claim 41, wherein said water-soluble molecule has either one acid group and at least one amino group, or more amino groups than acid groups.

49. The composition according to claim 41, wherein said water-soluble molecule is an amino-acid residue or a poly(amino acids) having a pKa between 6.0 and 8.4.

50. The composition according to claim 49, wherein said amino acid residue is selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), asparagine (ASN), and glutamine (GLN), or a mixture thereof.

51. The composition according to claim 41, wherein said water-soluble molecule is an amino acid residue selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), and glutamine (GLN), said amino acid residue being modified with a radical acetyl, t-butyl, benzyl, benzoyl, ethyl, formyl, or methyl.

52. The composition according to claim 41, wherein said water-soluble molecule is a polymer of at least one amino acid selected from the group consisting of alanine (ALA), histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), glutamine (GLN), glycine (GLY), hydroxyproline (HYP), isoleucine (ILE), leucine (LEU), norleucine (NLE), phenylalanine (PHE), proline (PRO), serine (SER), threonine (THR), tyrosine (TYR), and valine (VAL).

53. The composition according to claim 41, wherein said composition further comprises at least one other water-soluble polymer.

54. The composition according to claim 53, wherein said at least one other water-soluble polymer is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propyl cellulose, polyethylene oxide, polypropylene oxide, poly(ethylene oxide-co-propylene oxide) copolymers, poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) copolymers, polyvinyl alcohol, and polycaprolactone diols, and mixtures thereof.

55. The composition according to claim 41, further comprising a solid particulate or a water-soluble additive.

56. The composition according to claim 41, further comprising a drug or a pharmaceutical agent.

57. The composition according to claim 41, further comprising microorganisms, plant cells, animal cells or human cells dispersed therein.

58. The composition of claim 41, wherein said composition is loaded with cells selected from the group consisting of chondrocytes (articular cartilage), fibrochondrocytes (meniscus), ligament fibroblasts (ligament), skin fibroblasts (skin), tenocytes (tendons), myofibroblasts (muscle), mesenchymal stem cells and keratinocytes (skin).

59. A method for preparing a composition according to claim 41, which comprises the steps of:

a) dissolving a pH-gelling acid-soluble polymer within an aqueous acidic solution of a pH from about 1.0 to about 5.0 to obtain an aqueous polymer composition having a concentration of 0.1 to 10% by weight of said polymer, wherein said polymer is collagen;

b) dissolving 0.1 to 10% by weight of a water-soluble molecule having a pKa between 6.0 and 8.4 within said aqueous polymer composition to obtain a clear liquid formulation with a pH ranging between 5.8 and 7.4, said water-soluble molecule being free of salt of polyol and sugar;

c) heating said liquid formulation at a temperature above 30°

C. to obtain a solid gel, said gel having a pH from about 5.8 to about 7.4.

60. The method of claim 59, wherein said aqueous acidic solution is prepared from an organic or inorganic acid selected from the group consisting of acetic acid, ascorbic acid, glutamic acid, lactic acid, lactobionic acid, salicylic acid, phosphoric acid, hydrochloric acid, propionic acid, and formic acid, or a mixture thereof.

61. The method of claim 59, wherein said water-soluble molecule is an organic salt selected from the group consisting of a mono-phosphate salt, a mono-sulfonate salt, a mono-sulfate salt and a mono-carboxylate salt.

62. The method of claim 59, wherein said water-soluble molecule is selected from the group consisting of N-[carbamoylmethyl]-2-aminoethane sulfonate (ACES), N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonate (BES), 3-[N,N-bis(2-hydroxy-ethyl)amino]-2-hydroxypropanesulfonate (DIPSO), N-[2-hydroxyethyl]piperazine-N′

-3-propane-sulfonate (EPPS), N-[2-hydroxyethyl]piperazine-N′

-4-butane-sulfonate (HEPBS), N-[2-hydroxyethyl]piperazine-N′

-2-ethanesulfonate (HEPES), N-[2-hydroxyethyl]piperazine-N′

-2-hydroxypropanesulfonate (HEPSO), 2-[N-morpholino]ethanesulfonate (MES), 4-[N-morpholino]butanesulfonate (MOBS), 3-[N-morpholino]propanesulfonate (MOPS), 3-[N-morpholino]-2-hydroxypropanesulfonate (MOPSO), Piperazine-N,N′

-bis[2-ethanesulfonate] (PIPES), Piperazine-N,N′

-bis[2-hydroxypropanesulfonate] (POPSO), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonate (TAPSO), and N-tris[hydroxymethyl]methyl-2-aminoethanesulfonate (TES), and mixtures thereof.

63. The method of claim 59, wherein said water-soluble molecule is selected from the group consisting of N,N-bis[hydroxyethyl]glycine (BICINE), bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BIS-TRIS), Glycyl-glycine (GLY-GLY), Triethanolamine (TEA), N-tris[hydroxymethyl]methylglycine (TRICINE), and Tris[hydroxymethyl]aminomethane (TRIZMA), and mixtures thereof.

64. The method of claim 59, wherein said water-soluble molecule has either one acid group and at least one amino group, or more amino groups than acid groups.

65. The method of claim 59, wherein said water-soluble molecule is an amino-acid residue or a poly(amino acids) having a pKa between 6.0 and 8.4.

66. The method of claim 65, wherein said amino acid residue is selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), asparagine (ASN), glutamine (GLN), or a mixture thereof.

67. The method of claim 65, wherein said water-soluble molecule is an amino acid residue selected from the group consisting of histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), and glutamine (GLN) modified with a radical acetyl, t-butyl, benzyl, benzoyl, ethyl, formyl, or methyl.

68. The method of claim 59, wherein said water-soluble molecule is a polymer of at least one amino acid selected from the group consisting of alanine (ALA), histidine (HIS), arginine (ARG), lysine (LYS), aspartic acid (ASP), glutamine (GLN), glycine (GLY), hyroxyproline (HYP), isoleucine (ILE), leucine (LEU), norleucine (NLE), phenylalanine (PHE), proline (PRO), serine (SER), threonine (THR), tyrosine (TYR), and valine (VAL).

69. The method of claim 59, wherein said aqueous polymer composition turns into a gel at a temperature above 10°

C.

70. The method of claim 59, wherein said aqueous polymer composition turns into a gel at a temperature above 37°

C.

71. The method of claim 59, wherein said polymer solution further comprises a solid particulate additive, said solid particulate additive being added to the polymer solution of step a) or b).

72. The method of claim 59, further comprising another water-soluble polymer added to the polymer solution of step a) or b).

73. The method of claim 72, wherein said another polymer is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propyl cellulose, polyethylene oxide, polypropylene oxide, poly(ethylene oxide-co-propylene oxide) copolymers, poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) copolymers, polyvinyl alcohol, and polycaprolactone diols.