Method of controlling pharmacokinetics of immunomodulatory compounds

• US 20040082934A1
• Filed: 08/28/2003
• Published: 04/29/2004
• Est. Priority Date: 08/30/2002
• Status: Abandoned Application

• Current Assignee: Becton, Dickinson & Co
• Original Assignee: Becton, Dickinson & Co
• Inventors: Pettis, Ronald J.
• Application Number:
  US10/650,039
• Publication Number:
  US 20040082934A1
• Time in Patent Office: Days
• US Class Current: 604/506
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61P 37/02 Immunomodulators

Abstract

A method and device for administration of an immunomodulatory substance into skin.

Claims

22. A method of administering an immunomodulatory substance comprising injecting or infusing the substance intradermally through one or more microneedles having a length and outlet suitable for selectively delivering the substance into the dermis to obtain absorption of the substance in the dermis.

23. The method of claim 22 wherein absorption of the substance in the dermis produces improved systemic pharmacokinetics compared to subcutaneous administration.

24. The method of claim 23 wherein the improved pharmacokinetics is increased bioavalability.

25. The method of claim 23 wherein the improved pharmacokinetics is decreased T_max.

26. The method of claim 23 wherein the improved pharmacokinetics is an increase in C_max.

27. The method of claim 23 wherein the improved pharmacokinetics is a decrease in T_lag.

28. The method of claim 23 wherein the improved pharmacokinetics is an enhanced absorption rate.

29. The method of claim 22 wherein the length of the microneedle is from about 0.5 mm to about 1.7 mm.

30. The method of claim 22 wherein the microneedle is 30 gauge or narrower.

31. The method of claim 22 wherein the microneedle has an outlet of from 0 to 1 mm.

32. The method of claim 22 wherein the microneedle is configured in a delivery device which positions the microneedle perpendicular to skin surface.

33. The method of claim 22 wherein the microneedle needle is contained in an array of microneedles needles.

34. The method of claim 33 wherein the array comprises 3 microneedles.

35. The method of claim 33 wherein the array comprises 6 microneedles.

36. The method of claim 22 wherein said substance is an immunostimulant.

37. The method of claim 22 wherein said substance is an immunosuppressant.

38-1. The method of claim 38 wherein said substance is a lipopolysacharride or BCG, or a synthetic derivative thereof.

41. A method for delivering an immunomodulatory substance to a subject comprising:

contacting the skin of the subject with a device having a dermal-access means for accurately targeting the dermal space of the subject with an efficacious amount of the bioactive substance.

42. The method of claim 41 wherein the pharmacokinetics of the immunomodulatory substance is improved relative to the pharmacokinetics of the substance when administered subcutaneously.

43. The method of claim 42 wherein the improved pharmacokinetics is an increase in bioavailability.

44. The method of claim 42 wherein the improved pharmacokinetics is a decrease in T_max.

45. The method of claim 42 wherein the improved pharmacokinetics comprises an increase in C_max of the substance compared to subcutaneous injection.

46. The method of claim 42 wherein the improved pharmacokinetics is a decrease in T_lag.

47. The method of claim 42 wherein the improved pharmacokinetics is an enhanced absorption rate.

48. The method of claim 41 wherein the dermal access means comprises one or more hollow microcannula having a length of from about 0.3 to about 2 mm.

49. The method of claim 41 wherein said dermal access means comprises one or more hollow microcannula having an outlet with an exposed height between 0 and 1 mm.

50. The method of claim 41 wherein the substance is an immunostimulant.

51. The method of claim 41 wherein said substance is an immunosuppressant.

52. The method of claim 41 wherein said substance is selected from the group consisting of an interferon, an interleukin, an anti-inflammatory agent, a tumor targeting compound, and a bacterial cell wall component or synthetic derivative thereof.

53. The method of claim 52 wherein said substance is a lipopolysacharride or BCG, or a synthetic derivative thereof.

54. The method of claim 52 wherein the substance is a interferon.

55. A method for delivering an immunomodulatory substance into tissue comprising delivering the substance within or beneath the skin at least into the intradermal space to access one or more compartments, which compartments afford the substance different pharmacokinetics, which enhance the effectiveness of the substance in terms of a resultant composite pharmacokinetics.

56. The method of claim 55 wherein the substance is delivered to a site which includes two or more of the compartments.

57. The method of claim 55 wherein the substance is delivered to multiple sites which each include one or more of the compartments.

58. The method of claim 55 wherein the delivery of the substance is by a needle or cannula.

59. The method of claim 58 wherein a single needle is inserted into the intradermal space.

60. The method of claim 58 wherein multiple needles or needle arrays are inserted into the intradermal space.

61. The method of claim 60 wherein the multiple needles have different lengths.

62. The method of claim 58 wherein the needle is about 300 μ

m to about 5 mm long.

63. The method of claim 62 wherein the needle is about 500 μ

m to about 1 mm long.

64. The method of claim 59 wherein the needle has an outlet placed at a depth of about 300 μ

m to about 2 mm when the needle is inserted into the intradermal space.

66. The method of claim 64 wherein the outlet has an exposed height of about 0 to about 1 mm.

67. The method of claim 66 wherein the outlet has an exposed height of about 0 to about 300 μ

m.

68. The method of claim 55 wherein the delivery of the substance is by a needle selected from the group consisting of microneedles, catheter needles, and injection needles.

69. The method of claim 55 wherein said substance is an immunostimulant.

70. The method of claim 55 wherein said substance is an immunosuppressant.

71. The method of claim 55 wherein said substance is selected from the group consisting of an interferon, an interleukin, an anti-inflammatory agent, a tumor targeting compound, and a bacterial cell wall component or synthetic derivative thereof.

72. The method of claim 71 wherein said substance is a lipopolysacharride or BCG, or a synthetic derivative thereof.

73. The method of claim 71 wherein the substance is α

interferon.

74. The method of claim 55 wherein the substance is infused.

75. The method of claim 55 wherein the substance is delivered as a bolus.

76. The method of claim 55 further comprising controlling the delivery rate or volume delivered of the substance to the intradermal space.

77. The method of claim 55 wherein said delivery is controlled pursuant to an algorithm having logic components which include physiologic models, rules based models or moving average methods, therapy pharmacokinetic models, monitoring signal processing algorithms, predictive control models, or combinations thereof.

78. The method of claim 55 wherein the substance is infused at a constant rate.

79. The method of claim 55 wherein the substance is delivered by a combination of infusion and bolus injection.

80. The method of claim 55 wherein the multiple compartments are intradermal and subcutaneous tissue compartments.

81. The method of claim 55 wherein the access of the one or more compartments is by at least one needle that targets the ID compartment and at least another one needle that targets SC compartment.

82. The method of claim 55 wherein the delivery to the one or more compartments is by at least one needle which essentially simultaneously targets the ID compartment and SC compartment.

83. The method of claim 55 wherein the delivery of the one or more compartments is by at least one needle which sequentially targets the ID compartment and SC compartment.

84. The method of claim 55 wherein the delivery to multiple compartments is by at least one needle that targets the interface of the ID and SC compartments.

85. The method of claim 55 wherein a portion of said therapeutic substance is absorbed more rapidly into the intradermal tissue space, and the remaining portion is absorbed less rapidly into the subcutaneous tissue space.

86. The method of claim 55 wherein the enhanced effectiveness is a decrease in T_max.

87. The method of claim 55 wherein the enhanced effectiveness is an increase in C_max.

88. The method of claim 55 wherein the enhanced effectiveness is a decrease in T_lag.

89. The method of claim 55 wherein the enhanced effectiveness is enhanced absorption rate.

90. The method of claim 55 wherein the enhanced effectiveness is improved bioavailability.

65-2. The method of claim 65 wherein the outlet is at a depth of about 750 μ

m to about 1.5 mm when the needle is inserted.