Method and device for delivery of high molecular weight substances

• US 20050124967A1
• Filed: 12/28/2001
• Published: 06/09/2005
• Est. Priority Date: 10/14/1999
• Status: Abandoned Application

• Current Assignee: Diane E. Sutter, John Mikszta, Ronald J. Pettis, Scott A. Kaestner
• Original Assignee: Diane E. Sutter, John Mikszta, Ronald J. Pettis, Scott A. Kaestner
• Inventors: Sutter, Diane E., Pettis, Ronald J., Kaestner, Scott A., Mikszta, John
• Application Number:
  US10/487,485
• Publication Number:
  US 20050124967A1
• Time in Patent Office: Days
• US Class Current: 604/506
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61M 2037/0046 Solid microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 2202/0445 Proteins
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61M 5/158 Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
• CPC Class Codes: A61M 5/282 by compression of deformable ampoule or carpule wall
• CPC Class Codes: A61M 5/30 Syringes for injection by jet action, without needle, e.g. for use with replaceable ampoules or carpules
• CPC Class Codes: A61M 5/3202 Devices for protection of the needle before use, e.g. caps A61M5/50 takes precedence; for infusion spikes A61M5/1626; protectors for sharps A61B50/3001
• CPC Class Codes: A61M 5/3278 Apparatus for destroying used needles or syringes needle resheathing means destroying the needle A61M5/321
• CPC Class Codes: A61M 5/46 having means for controlling depth of insertion

Abstract

A method and device for administration of a high molecular weight protein into the intradermal space.

Claims

1. A method for directly delivering a high molecular weight substance into an intradermal space within mammalian skin comprising administering the substance through at least one hollow needle having an outlet with an exposed height between 0 and 1 mm, said outlet being inserted into the skin to a depth of between 0.3 mm and 2 mm, such that delivery of the substance occurs at a depth between 0.3 mm and 2 mm.

2. The method according to claim 1 wherein the delivered substance has improved pharmacokinetics compared to pharmacokinetics after subcutaneous injection.

3. The method of claim 1 wherein the administration is through at least one small gauge hollow needle.

4. The method of claim 1 wherein the needle has an outlet with an exposed height between 0 and 1 mm.

5. The method of claim 1 wherein injecting comprises inserting the needle to a depth which delivers the substance at least about 0.3 mm below the surface to no more than about 2 mm below the surface.

6. The method of claim 1 wherein administering comprises inserting the needle into the skin to a depth of at least about 0.3 mm and no more than about 2 mm.

7. The method of claim 2 wherein the improved pharmacokinetics is increased bioavailability of the substance.

8. The method of claim 2 wherein the improved pharmacokinetics is a decrease in T_max.

9. The method of claim 2 wherein the improved pharmacokinetics is an increase in C_max.

10. The method of claim 2 wherein the improved pharmacokinetics is a decrease in T_lag.

11. The method of claim 2 wherein the improved pharmacokinetics is enhanced absorption rate.

12. The method of claim 1 wherein the substance is administered over a time period of not more than ten minutes.

13. The method of claim 1 wherein the substance is administered over a time period of greater than ten minutes.

14. The method of claim 1 wherein the substance is a protein.

15. The method of claim 1 wherein the substance is administered at a rate between 1 nL/min. and 200 mL/min.

16. The method of claim 1 wherein said substance is a hormone.

17. The method of claim 14 wherein said protein is a receptor protein or antibody.

18. The method of claim 17 wherein said protein is etanercept.

19. The method of claim 14 wherein said protein is a fusion protein.

20. The method of claim 1 wherein said substance has a molecular weight of at least 40,000 kD.

21. The method of claim 20 wherein said substance has a molecular weight of at least 100,000 kD.

22. The method of claim 21 wherein said substance has a molecular weight of at least 150,000 kD.

23. The method of claim 1 wherein said substance is a nucleic acid.

24. The method of claim 1 wherein said substance is hydrophobic.

25. The method of claim 1 wherein said substance is hydrophilic.

26. The method of claim 1 wherein the needle(s) are inserted substantially perpendicularly to the skin.

27. The method of claim 1 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed.

28. A method of administering a pharmaceutical 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.

29. The method of claim 28 wherein absorption of the substance in the dermis produces improved systemic pharmacokinetics compared to subcutaneous administration.

30. The method of claim 29 wherein the improved pharmacokinetics is increased bioavailability.

31. The method of claim 29 wherein the improved pharmacokinetics is decreased T_max.

32. The method of claim 29 wherein the improved pharmacokinetics is an increase in C_max.

33. The method of claim 29 wherein the improved pharmacokinetics is a decrease in T_lag.

34. The method of claim 29 wherein the improved pharmacokinetics is an enhanced absorption rate.

35. The method of claim 28 wherein the length of the microneedle is from about 0.5 mm to about 1.7 mm.

36. The method of claim 28 wherein the microneedle is 30 gauge or narrower.

37. The method of claim 28 wherein the microneedle has an outlet of from 0 to 1 mm.

38. The method of claim 28 wherein the microneedle is configured in a delivery device which positions the microneedle perpendicular to skin surface.

39. The method of claim 28 wherein the microneedle needle is contained in an array of microneedles needles.

40. The method of claim 39 wherein the array comprises 3 microneedles.

41. The method of claim 39 wherein the array comprises 6 microneedles.

42. The method of claim 28 wherein the substance has a molecular weight of at least 40 kD.

43. The method of claim 42 wherein the substance is a protein.

44. The method of claim 43 wherein said protein is a receptor protein or antibody.

45. The method of claim 44 wherein said protein is etanercept.

46. The method of claim 28 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed.

47. A microneedle for intradermal injection of a high molecular weight pharmaceutical substance, wherein the microneedle has a length and outlet selected for its suitability for specifically delivering the substance into the dermis.

48. The microneedle according to claim 47 wherein the length of the microneedle is from about 0.5 mm to about 1.7 mm.

49. The microneedle of claim 47 which is a 30 gauge or narrower.

50. The microneedle of claim 47 which has an outlet of from 0 to 1 mm.

51. The microneedle of claim 47 which is configured in a delivery device which positions the microneedle perpendicular to skin surface.

52. The microneedle of claim 47 which is in an array of microneedles needles.

53. The microneedle of claim 52 wherein the array comprises 3 microneedles.

54. The microneedle of claim 52 wherein the array comprises 6 microneedles.

55. A method for delivering a bioactive 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.

56. The method of claim 55 wherein the pharmacokinetics of the bioactive substance is improved relative to the pharmacokinetics of the substance when administered subcutaneously.

57. The method of claim 56 wherein the improved pharmacokinetics is an increase in bioavailability.

58. The method of claim 56 wherein the improved pharmacokinetics is a decrease in T_max.

59. The method of claim 56 wherein the improved pharmacokinetics comprises an increase in C_max of the substance compared to subcutaneous injection.

60. The method of claim 56 wherein the improved pharmacokinetics is a decrease in T_lag.

61. The method of claim 56 wherein the improved pharmacokinetics is an enhanced absorption rate.

62. The method of claim 55 wherein the device has a fluid driving means including a syringe, infusion pump, piezoelectric pump, electromotive pump, electromagnetic pump, or Belleville spring.

63. The method of claim 55 wherein the dermal access means comprises one or more hollow microcannula having a length of from about 0.5 to about 1.7 mm.

64. The method of claim 55 wherein said dermal access means comprises one or more hollow microcannula having an outlet with an exposed height between 0 and 1 mm.

65. The method of claim 55 wherein the substance has a molecular weight of at least 40 kD.

66. The method of claim 55 wherein the substance is or protein.

67. The method of claim 66 wherein said protein is a receptor protein or antibody.

68. The method of claim 67 wherein said protein is etanercept.

69. The method of claim 55 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed.

70. A method for delivering a high molecular weight bioactive substance to a subject comprising:

contacting the skin of a 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 at a rate of 1 nL/min. to 200 mL/min.

71. The method of claim 70 wherein the rapid onset pharmacokinetics of the bioactive substance is substantially improved relative to subcutaneous injection.

72. The method of claim 71 wherein the bioavailability is increased.

73. The method of claim 71 wherein the pharmokinetics is a decreased T_max.

74. The method of claim 71 wherein the pharmokinetics is an increased C_max.

75. The method of claim 71 wherein the pharmokinetics is a decreased T_lag.

76. The method of claim 71 wherein the pharmacokinetics is an enhanced absorption rate.

77. The method of claim 70 wherein the dermal access means has one or more hollow microcannula that inserts into the skin of said subject to a depth of from about 0.5 to about 2.0 mm.

78. The method of claim 70 wherein the dermal access means has one or more hollow microcannula having an outlet with an exposed height between 0 and 1 mm.

79. The method of claim 70 wherein said substance has a molecular weight of at least 40 kD.

80. The method of claim 70 wherein said substance is a protein.

81. The method of claim 80 wherein said protein is a receptor protein or antibody.

82. The method of claim 80 wherein said protein is etanercept.

83. The method of claim 70 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed.

84. The method of claim 80 wherein said protein is a fusion protein.

85. The method of claim 70 wherein said substance has a molecular weight of at least 100,000 kD.

86. The method of claim 85 wherein said substance is a protein.

87. The method of claim 85 wherein said substance has a molecular weight of at least 150 kD.

88. The method of claim 87 wherein said substance is a protein.