Method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen

• US 4,690,825 A
• Filed: 10/04/1985
• Issued: 09/01/1987
• Est. Priority Date: 10/04/1985
• Status: Expired due to Term

• Current Assignee: Advanced Polymer Systems Incorporated 3696c Haven Avenue Redwood City CA 94063
• Original Assignee: Advanced Polymer Systems Incorporated
• Inventors: Won, Richard
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US06/784,382
• Time in Patent Office: 697 Days
• Field of Search: 424/22, 514/963, 514/965, 521/63
• US Class Current: 424/501
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: C08J 9/28 by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
• CPC Class Codes: C08J 9/286 the liquid phase being a solvent for the monomers but not for the resulting macromolecular composition, i.e. macroporous or macroreticular polymers

Abstract

Delivery vehicles comprised of a polymeric bead having a network of pores with an active ingredient held within the network are provided for use in a method to provide controlled release of the active ingredient. The network of pores is substantially non-collapsible upon removal of the active ingredient and the delivery vehicles are polymerized by a process in which the active ingredient also comprises the porogen during formation of the network of pores.

Claims

1. A composition of matter useful as a time-release delivery vehicle for delivering an active ingredient by controlled time release, comprising a porous polymeric bead having a network of pores with the active ingredient held within the network of pores, said network of pores being substantially non-collapsible upon removal of the active ingredient.

2. A composition of matter as recited in claim 1 wherein the bead is copolymerized from a comonomer pair selected from the groups consisting of vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethylmethacrylate.

3. A composition of matter as recited in claim 1 wherein the bead has a diameter from about 10 microns to about 100 microns.

4. A composition of matter as recited in claim 1 wherein the active ingredient is a porogen.

5. A composition of matter as recited in claim 4 wherein the porogen is comprised of mineral oil.

6. A composition of matter as recited in claim 1 wherein the bead has a calculated cross-linking density in excess of about 10%.

7. A composition of matter as recited in claim 1 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the composition.

8. A process for preparing a time-release delivery vehicle useful for delivering an active ingredient by controlled release, comprising the steps of:

dissolving at least one monomer in an inert porogen to form a solution;

suspending the solution in a phase incompatible with the solution;

agitating the solution and the phase to form a plurality of droplets of the solution suspended in the phase;

activating at least one monomer in the plurality of droplets to polymerize at least one monomer and form a porous bead having a network of pores with the porogen held within the network of pores, said network of pores being substantially non-collapsible upon removal of the porogen;

separating the porous polymeric bead from the phase;

removing any impurity from the porous polymeric bead; and

retaining the porogen within the network of pores as the active ingredient to form the delivery vehicle.

9. A process as recited in claim 8 wherein one monomer is cross-linked to form the porous bead.

10. A process as recited in claim 8 wherein a comonomer pair is copolymerized to form the bead, said comonomer pair being selected from the groups consisting of vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethylmethacrylate.

11. A process as recited in claim 8 wherein the porogen is mineral oil.

12. A process as recited in claim 8 wherein the polymeric bead has a diameter from about 10 microns to about 100 microns.

13. A process as recited in claim 8 wherein the polymeric bead has a calculated cross-linking density in excess of about 10%.

14. A process as recited in claim 10 wherein the comonomer pair is styrene and divinylbenzene which are activated by an initiator which is soluble in styrene and divinylbenzene.

15. A process as recited in claim 10 wherein the comonomer pair is activated by an initiator which is soluble in the comonomer pair.

16. A method for delivering an active ingredient by controlled time release, comprising the steps of:

mixing a delivery vehicle with a medium to form a mixture, said delivery vehicle comprising a porous polymeric bead having a network of pores with the active ingredient held within the network of pores said network of pores being substantially non-collapsible upon removal of the active ingredient;

applying the mixture to a surface; and

releasing the active ingredient from the network of pores.

17. A method as recited in claim 16 wherein the delivery vehicle has a diameter from about 10 microns to about 100 microns.

18. A method as recited in claim 16 wherein the active ingredient is a porogen.

19. A method as recited in claim 18 wherein the porogen is comprised of mineral oil.

20. A method as recited in claim 16 wherein the delivery vehicle has a calculated cross-linking density in excess of about 10%.

21. A method as recited in claim 16 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the delivery vehicle.

22. A method as recited in claim 16 wherein the active ingredient is released by pressure.

23. A method as recited in claim 16 wherein the active ingredient is released by diffusion.

24. A method as recited in claim 16 wherein the active ingredient is released by volatization.

25. A method as recited in claim 22 wherein the active ingredient is gradually and continuously released from the network of the pores.

26. A method as recited in claim 16 wherein the active ingredient is comprised of a carrier and an agent.

27. A method as recited in claim 16 wherein the polymeric bead is copolymerized from a comonomer pair selected from the groups consisting of vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethylmethacrylate.

28. A composition of matter useful as a time-release delivery vehicle for delivering an active ingredient by controlled time release, comprising a porous polymeric bead of styrene divinylbenzene having a network of pores with the active ingredient held within the network of pores, said network of pores being substantially non-collapsible upon removal of the active ingredient.

29. A composition of matter as recited in claim 28 wherein the bead has a diameter from about 10 microns to about 100 microns.

30. A composition of matter as recited in claim 28 wherein the active ingredient is a porogen.

31. A composition of matter as recited in claim 30 wherein the porogen is comprised of mineral oil.

32. A composition of matter as recited in claim 28 wherein the bead has a calculated cross-linking density in excess of about 10%.

33. A composition of matter as recited in claim 28 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the composition.

34. A process for preparing a time-release delivery vehicle useful for delivering an active ingredient by controlled time-release, comprising the steps of:

dissolving styrene and divinylbenzene in an inert porogen to form a solution;

suspending the solution in a phase incompatible with the solution;

agitating a plurality of the solution and the phase to form droplets of the solution suspended in the phase;

activating styrene and divinylbenzene in the plurality of droplets to copolymerize the styrene and divinylbenzene and form at least one porous polymeric bead of styrene divinylbenzene having a network of pores with the porogen held within the network of pores, said network of pores being substantially non-collapsible upon removal of the porogen;

separating the porous polymeric bead from the phase;

removing any impurity from the porous polymeric bead; and

retaining the porogen within the network of pores as the active ingredient to form the time-release delivery vehicle.

35. A process as recited in claim 34 wherein the porogen is mineral oil.

36. A process as recited in claim 34 wherein the polymeric bead has a diameter from about 10 microns to about 100 microns.

37. A process as recited in claim 34 wherein the polymeric bead has a calculated cross-linking density in excess of about 10%.

38. A process as recited in claim 34 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the delivery vehicle.

39. A process as recited in claim 34 wherein the styrene and divinylbenzene are activated by an initiator which is soluble in styrene and divinylbenzene.

40. A method for delivering an active ingredient by controlled time release;

comprising the steps of;

mixing a delivery vehicle with a medium to form a mixture, said delivery vehicle comprising a porous polymeric bead of styrene divinylbenzene having a network of pores with the active ingredient held within the network of pores, said network of pores being substantially non-collapsible upon removal of the active ingredient;

applying the mixture to a surface; and

releasing the active ingredient from the network of pores.

41. A method as recited in claim 40 wherein the delivery vehicle has a diameter from about 10 microns to about 100 microns.

42. A method as recited in claim 40 wherein the active ingredient is a porogen.

43. A method as recited in claim 42 wherein the porogen is comprised of mineral oil.

44. A method as recited in claim 40 wherein the delivery vehicle has a calculated cross-linking density in excess of about 10%.

45. A method as recited in claim 40 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the delivery vehicle.

46. A method as recited in claim 40 wherein the active ingredient is released by pressure.

47. A method as recited in claim 40 wherein the active ingredient is released by diffusion.

48. A method as recited in claim 40 wherein the active ingredient is released by volatization.

49. A method as recited in claim 46 wherein the active ingredient is gradually and continuously released from the network of the pores.

50. A method as recited in claim 40 wherein the active ingredient is comprised of a carrier and an agent.

51. A composition of matter useful as a time-release delivery vehicle for delivering an active ingredient by controlled time release, comprising a porous polymeric bead having a network of pores with the active ingredient held within the network of pores, said composition having a calculated cross-linking density and an active ingredient concentration such that substantially all of the active ingredient will be released from the network of pores when the bead is placed in a solvent in which the active ingredient is soluble for a sufficient length of time to wet the bead.

52. A composition of matter as recited in claim 51 wherein substantially all of the active ingredient will be released from the network of pores within about 5 minutes with moderate agitation of the solvent and the composition.

53. A composition of matter as recited in claim 51 wherein the bead is polymerized from a comonomer pair selected from the groups consisting of styrene and divinylbenzene, vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethacrylate.

54. A composition of matter as recited in claim 53 wherein the active ingredient is mineral oil.

55. A composition of matter as recited in claim 51 wherein the active ingredient is a porogen.

56. A composition of matter as recited in claim 55 wherein the active ingredient is mineral oil.

57. A composition of matter as recited in claim 51 wherein the bead has a diameter from about 10 microns to about 100 microns.

58. A composition of matter as recited in claim 51 wherein the bead has a calculated cross-linking density in excess of about 10%.

59. A composition of matter as recited in claim 51 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the composition.

60. A process for preparing a time-release delivery vehicle useful for delivering an active ingredient by controlled time-release, comprising the steps of:

dissolving at least one monomer in an inert porogen to form a solution;

suspending the solution in a phase incompatible with the solution;

agitating the solution and the phase to form a plurality of droplets of the solution suspended in the phase;

activating at least one monomer in the plurality of droplets to polymerize at least one monomer and form a porous bead having a network of pores with the porogen held within the network of pores;

separating the porous polymeric bead from the phase;

removing any impurity from the porous polymeric bead; and

retaining the porogen within the network of pores as the active ingredient to form the delivery vehicle, said delivery vehicle having a calculated cross-linking density and an active ingredient concentration such that substantially all of the active ingredient will be released from the network of pores when the bead is placed in a solvent in which the active ingredient is soluble for a sufficient length of time to wet the bead.

61. A process as recited in claim 60 wherein a comonomer pair is polymerized to form the bead, said comonomer pair being selected from the groups consisting of styrene and divinylbenzene, vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethymethacrylate.

62. A process as recited in claim 61 wherein the comonomer pair is activated by an initiator which is soluble in the comonomer itself.

63. A process as recited in claim 61 wherein the porogen is mineral oil.

64. A process as recited in claim 60 wherein a comonomer pair is copolymerized to form the bead, said comonomer pair being selected from the groups consisting of vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethymethacrylate.

65. A process as recited in claim 60 wherein the polymeric bead has a diameter from about 10 microns to about 100 microns.

66. A process as recited in claim 60 wherein the polymeric bead has a calculated cross-linking density in excess of about 10%.

67. A process as recited in claim 60 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the delivery vehicle.

68. A method for delivering an active ingredient by controlled time release, comprising the steps of:

mixing a delivery vehicle with a medium to form a mixture, said delivery vehicle comprising a porous polymeric bead having a network of pores with the active ingredient held within the network of pores, said delivery vehicle having a calculated cross-linking density and an active ingredient concentration such that substantially all of the active ingredient will be released from the network of pores when the bead is placed in a solvent of pores in which the active ingredient is soluble for a sufficient length of time to wet the bead;

applying the mixture to a surface; and

releasing the active ingredient from the network of pores.

69. A method as recited in claim 68 wherein the polymeric bead is copolymerized from a comonomer pair selected from the groups consisting of styrene and divinylbenzene, vinyl stearate and divinylbenzene, and methylmethacrylate and ethylene glycol dimethylmethacrylate.

70. A method as recited in claim 69 wherein the active ingredient is comprised of mineral oil.

71. A method as recited in claim 68 wherein the delivery vehicle has a diameter from about 10 microns to about 100 microns.

72. A method as recited in claim 68 wherein the active ingredient is a porogen.

73. A method as recited in claim 72 wherein the porogen is comprised of mineral oil.

74. A method as recited in claim 68 wherein the delivery vehicle has a calculated cross-linking density in excess of about 10%.

75. A method as recited in claim 68 wherein the active ingredient comprises between approximately 5% to approximately 60% of the total weight of the delivery vehicle.

76. A method as recited in claim 68 wherein the active ingredient is released by pressure.

77. A method as recited in claim 76 wherein the active ingredient is gradually and continuously released from the network of the pores.

78. A method as recited in claim 68 wherein the active ingredient is released by diffusion.

79. A method as recited in claim 68 wherein the active ingredient is released by volatization.

80. A method as recited in claim 68 wherein the active ingredient is comprised of a carrier and an agent.