Increased bioavailability of transdermally delivered agents
A method for delivering a bioactive agent to the cardiovascular system is described. The method delivers the agent at a high bioavailability and with little loss of agent to the natural defense mechanisms of the body. For instance, little or none of the bioactive agent will be sequestered in lymph tissue and prevented from circulation in the cardiovascular system. The method includes utilization of a transdermal delivery device including microneedles with structures fabricated on a surface of the microneedles to form a nanotopography. A random or non-random pattern of structures may be fabricated such as a complex pattern including structures of differing sizes and/or shapes.
1. A method for delivering a bioactive agent to a subject comprising:
penetrating the stratum corneum of the subject with a microneedle that contains a channel in fluid communication with the bioactive agent, the microneedle including a plurality of nanostructures and microstructures formed on an external surface thereof in a pattern, wherein at least a portion of the microstructures have a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, the cross-sectional dimension of the microstructures being greater than the height of the microstructures, and wherein at least a portion of the nanostructures have a cross-sectional dimension of greater than about 5 nanometers and less than about 500 nanometers;
transporting the bioactive agent through the channel of the microneedle, wherein the channel is surrounded by the external surface of the microneedle; and
delivering the bioactive agent to the subject with a comparative bioavailability as compared to subcutaneous delivery of greater than about 20%.
2. The method according to claim 1 , wherein the bioactive agent is delivered to the subject such that the concentration of the bioactive agent in lymph node tissue of the subject is less than about 50 nanograms per gram of the lymph node tissue about 72 hours after penetrating the stratum corneum of the subject.
3. The method according to claim 1 , wherein the concentration of the bioactive agent in the lymph node is less than about 10 nanograms per gram of the lymph node about 72 hours after the application of the transdermal delivery device to the skin surface.
4. The method according to claim 1 , wherein the concentration of the bioactive agent in the lymph node is less than about 1 nanogram per gram of the lymph node about 72 hours after the application of the transdermal delivery device to the skin surface.
5. The method according to claim 1 , the subject having a spleen, wherein the concentration of the bioactive agent in a sample of the spleen tissue is less than about 5 nanograms per gram of the sample of the spleen tissue about 72 hours after the application of the transdermal delivery device to the skin surface.
6. The method according to claim 5 , wherein the concentration of the bioactive agent in a sample of the spleen tissue is less than about 1 nanogram per gram of the sample of the spleen tissue about 72 hours after the application of the transdermal delivery device to the skin surface.
7. The method according to claim 1 , the subject having a liver, wherein the concentration of the bioactive agent in a sample of the liver tissue is less than about 50 nanograms per gram of the sample of liver tissue about 72 hours after the application of the transdermal delivery device to the skin surface.
8. The method according to claim 7 , wherein the concentration of the bioactive agent in a sample of the liver tissue is less than about 1 nanogram per gram of the sample of the liver tissue about 72 hours after the application of the transdermal delivery device to the skin surface.
9. The method according to claim 1 , further comprising second nanostructures having a cross-sectional dimension less than the cross-sectional dimension of the microstructures and greater than the cross-sectional dimension of the plurality of nanostructures.
10. The method according to claim 1 , wherein the stratum corneum is a layer of the subject's skin, the skin including tight junctions between cells of the skin, the nanostructures rearranging tight junctions between the cells, thereby increasing porosity of the skin.
11. The method according to claim 10 , wherein the rearrangement of the tight junctions leads to an increase in the porosity of a second tissue type that is not in contact with the microneedle.
12. The method according to claim 11 , wherein the second tissue type is vascular tissue.
13. The method according to claim 1 , wherein the pattern has a fractal dimension of greater than about 1.
14. The method according to claim 1 , wherein the pattern has a fractal dimension of from about 1.5 to about 2.5.
15. The method according to claim 1 , wherein the microneedle surface containing the plurality of nanostructures has an average surface roughness between about 10 nanometers and about 200 nanometers.
16. The method according to claim 1 , wherein the microneedle surface containing the plurality of nanostructures has an effective shear modulus between about 4 MPa and about 320 MPa.
17. The method according to claim 1 , wherein the bioactive agent has a molecular weight of greater than about 100 kDa.
18. The method according to claim 17 , wherein the bioactive agent is a protein therapeutic.
19. The method according to claim 1 , wherein the channel has a cross-sectional dimension of from about 1 to about 100 micrometers.
20. The method according to claim 19 , wherein the channel has a length of from about 10 to about 800 micrometers.
21. The method according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 20 to about 400 nanometers and at least a portion of the microstructures have a cross-sectional dimension of from about 600 nanometers to about 1.5 micrometers.
22. The method according to claim 1 , wherein the nanostructures have approximately the same cross-sectional dimension.
23. The method according to claim 1 , wherein the ratio of the cross sectional dimension of two adjacent nanostructures to the center-to-center spacing between those two structures is between about 1:1 and about 1:4.
24. The method according to claim 1 , wherein at least a portion of the nanostructures have an equidistant spacing.
25. The method according to claim 1 , where at least a portion of the nanostructures have a height of from about 20 nanometers to about 1 micrometer.
26. The method according to claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.2 to about 5.
27. The method according to claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.5 to about 3.5.
28. The method according to claim 1 , wherein at least a portion of the microstructures have an aspect ratio of from about 0.15 to 1.
29. The method according to claim 1 , wherein at least a portion of the nanostructures have a center-to-center spacing of from about 50 nanometers to about 1 micrometer.
30. The method according to claim 1 , wherein the nanostructures are in the form of pillars, the pillars having a base adjacent to the external surface of the microneedle and extending in a generally longitudinal direction to a tip.
31. The method according to claim 1 , wherein at least a portion of the nanostructures have a height greater than a cross-sectional dimension.