Random block copolymers

• US 20040198901A1
• Filed: 03/22/2004
• Published: 10/07/2004
• Est. Priority Date: 04/01/1993
• Status: Active Grant

• Current Assignee: Ocutec Ltd
• Original Assignee: BTG International Limited (Boston Scientific Corporation)
• Inventors: Graham, Neil Bonnette, Moran, Christopher Raymond
• Granted Patent: US 7,241,845 B2
• Time in Patent Office: Days
• US Class Current: 524/589
• 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: C08G 18/4808 Mixtures of two or more polyetherdiols
• CPC Class Codes: C08G 18/6685 with compounds of group C08G18/3225 or polyamines of C08G18/38
• CPC Class Codes: C08G 2210/00 Compositions for preparing hydrogels
• CPC Class Codes: C08G 65/33348 containing isocyanate group
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42
• CPC Class Codes: C08G 81/024 Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G

Abstract

A linear random block copolymer comprising segments of polyethylene oxide and a relatively more hydrophobic polymer, e.g. polypropylene oxide connected by hydrophobic segments containing urethane and urea groups formed from the reaction of a di-isocyanate and a diamine, wherein the diamine comprises less than 2% by weight of the total weight of the reactants used in the preparation of the copolymer.

Claims

1-38. -38 (cancelled).

39. An organic solvent-soluble linear random block copolymer hydrogel comprising hydrophilic predominantly polyethylene oxide segments —

(CH₂pCH₂O)—

, polymeric segments of more hydrophobic character than said polyethylene oxide segments, and hydrophobic segments containing urethane —

NHCOO—

groups and urea —

NHCONH—

groups connecting said hydrophilic and said more hydrophobic segments, in which the urea groups comprise from 0.1 to 5.0% by weight of the polymer.

40. A copolymer according to claim 39, in which said hydrophilic segments comprise predominantly polyethylene oxide (PEO) residues and a minor amount of an additional component derived from other alkylene oxides, epihalohydrins, cyclic mono or poly ethers and N-[epoxy substituded] heterocyclic compounds.

41. A copolymer according to claim 40, in which said polyether is selected from the group consisting of oxetane, tetrahydrofuran, dihydropyran, dioxolane and trioxane.

42. A copolymer according to claim 40, in which said heterocyclic compound is N-[2,3-epoxy-propyl] pyrrolidone.

43. A copolymer according to claim 40, in which the hydrophilic segment contains up to 25% by weight of groups derived from propylene oxide, 1,2, epoxybutane or 2,3, epoxybutane.

44. A copolymer according to claim 39, in which the more hydrophobic segments are derived from a polymer which is sufficiently compatible with the polyethylene oxide (PEO) to form a homogeneous melt or solution of the component polymers from which the copolymer product can be formed by a polymerization reaction.

45. A copolymer according to claim 39, in which the more hydrophobic segments comprise polypropylene oxide (PPO) segments —

(CH(CH₃)CH₂O)—

.

46. A copolymer according to claim 39, in which the relative proportions of the hydrophilic PEO segments and the more hydrophobic segments, are from 5 to 90% by weight of the total copolymer of PEO and 55 to 5% by weight of the total copolymer of the more hydrophobic segments.

47. A copolymer according to claim 39, in which the relative proportions of the hydrophilic PEO segments and the relatively more hydrophobic segments are from 30 to 60% by weight of the total copolymer of PEO and from 45 to 15% by weight of the total copolymer of the more hydrophobic segments.

48. A copolymer according to claim 39, wherein the polyethylene oxide segments are comprised of homopolymeric polyethylene oxide having a number average molecular weight of from 1,000 to 20,000.

49. A copolymer according to claim 45, wherein the polypropylene oxide segments are comprised of homopolymeric polypropylene oxide having a number average molecular weight of from 250 to 6,000.

50. A copolymer according to claim 39, in which the more hydrophobic segments are derived from a hydroxy or amine terminated polyol derived from polytetramethylene oxide, polyisobutylene, polyethylene adipate, polytetramethylene adipate, polycaprolactone, polybutadiene and hydrobutyl terminated polydimethylsiloxane.

51. A copolymer according to claim 39, comprising units of the formula

X—

OOCNH—

R—

NHCONH—

R′

—

NHCONH—

R—

NHCOO—

Y

wherein X represents a polyethylene oxide region, Y represents a polypropylene oxide region and R and R═

which may be the same or different represent hydrocarbyl groups comprising from 2 to 20 carbon atoms.

52. A copolymer according to claim 39, comprising units of the formula

X—

NHCONH—

(R″

)_a—

NHCONH—

Y

wherein X represents a hydrophilic polyethylene oxide segment, Y represents a polypropylene oxide region, a is 0 or 1 and R″

represents a hydrocarbyl group comprising from 2 to 20 carbon atoms.

53. A copolymer according to claim 51, wherein R represents an aliphatic group and R═

represents an aromatic group.

54. A copolymer according to claim 53, wherein R═

is a 1,2-cyclohexylene or 4,4′

-diphenylmethane group.

55. A copolymer according to claim 53, wherein R is a hexamethylene, isophorone or 4,4′

-dicyclohexylmethane group.

56. A copolymer according to claim 52, wherein R@ represents a group having the formula

[R—

X—

R]-n or [R—

Y—

R]-m

wherein R represents a hydrocarbyl group having from 2 to 20 carbon atoms, X represents a polyethylene oxide group, Y represents polypropylene oxide group and n and m being an integer having a value of at least 1, n and m being the same or different.

57. A copolymer according to claim 56, wherein R represents a hexamethylene, isophorone or 4,4′

-dicyclohexylmethane group.

58. A one-step process for preparing a linear random block copolymer according to claim 39, which comprises reacting a hydrophilic copolymer consisting predominantly of polyethylene oxide with a more hydrophobic polymer and a di-isocyanate, the amount of di-isocyanate being in excess of the stoichiometric amount required to produce the urethane and urea linkages, said reaction being conducted in the presence of reactive amino groups, the amino groups being provided by an added diamine reagent, when the reacting polymers are both hydroxy-terminated, or by one or more of the reacting polymers themselves when these are terminated by at least one amino group, the amount of reactive amino groups being no greater than that corresponding to those provided by 2% by weight of the added diamine, based on the total weight of reactants used.

59. A process according to claim 58, in which the more hydrophobic polymer is a polypropylene oxide.

60. A process according to claim 58, which is carried out in the absence of a solvent.

61. A process according to claim 58, wherein the excess amount of di-isocyanate R(NCO)₂ is from at least 1 to 10% over the amount needed so as to satisfy the stoichiometric requirement of one functional group per active hydrogen atom of the total reactants.

62. A random block copolymer whenever produced by a process according to claim 58.

63. An organic solvent solution of a copolymer according to claim 39.

64. A aqueous emulsion of a copolymer according to claim 39.

65. A controlled release composition which comprises a copolymer according to claim 39 in admixture with an active substance.

66. A composition according to claim 65, wherein the active substance is dispersed in the polyethylene oxide or polypropylene oxide.

67. A composition according to claim 65, wherein the active substance is biologically active substance.

68. A composition according to claim 67, wherein the active substance is one which is physiologically active in man.

69. A composition according to claim 65, wherein the polymer is in solution.

70. A composition according to claim 69, wherein the active substance is dissolved in the solution.

71. A composition according to claim 69, wherein the active substance is dispersed in the polymer solution.

72. A process for the production of a controlled release composition according to claim 65, which comprises dry mixing the active material with the copolymer and forming the composition by a compression molding, injection molding or extrusion step.

73. Shaped articles prepared from a copolymer of claim 39.

74. Articles coated with a copolymer according to claim 39.

75. A copolymer according to claim 39, complexed with polyacrylic acid, polymethacrylic acid or other polyacid.