Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1997-06-17
2001-05-08
Seidel, Richard K. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S046000, C600S573000
Reexamination Certificate
active
06230051
ABSTRACT:
TECHNICAL FIELD
The present invention relates to transdermal agent delivery and sampling. More particularly, this invention relates to the transdermal delivery of agents, such as peptides and proteins, as well as the transdermal sampling of agents, such as glucose, body electrolytes and substances of abuse, such as but not limited to alcohol and illicit drugs. The present invention uses skin-piercing microblades to enhance the transdermal flux of the agents during transdermal delivery or sampling.
BACKGROUND ART
Interest in the percutaneous or transdermal delivery of peptides and proteins to the human body continues to grow with the increasing number of medically useful peptides and proteins becoming available in large quantities and pure form. The transdermal delivery of peptides and proteins still faces significant problems. In many instances, the rate of delivery or flux of polypeptides through the skin is insufficient to produce a desired therapeutic effect due to the binding of the polypeptides to the skin. In addition, polypeptides and proteins are easily degraded during and after penetration into the skin, prior to reaching target cells. Likewise, the passive flux of water soluble small molecules such as salts is limited.
One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface or on “electrotransport”. “Electrotransport” refers generally to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or enhanced by the application of an electrical potential, which results in the application of electric current, which delivers or enhances delivery of the agent. The electrotransport of agents through a body surface may be attained in various manners. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying a high voltage electrical pulse to a membrane. In many instances, more than one of these processes may be occurring simultaneously to different extents. Electrotransport delivery generally increases agent delivery, particularly large molecular weight species (e.g., polypeptides) delivery rates, relative to passive or non-electrically assisted transdermal delivery. However, further increases in transdermal delivery rates and reductions in polypeptide degradation during transdermal delivery are highly desirable.
One method of increasing the agent transdermal delivery rate involves pre-treating the skin with, or alternatively co-delivering with the beneficial agent, a skin permeation enhancer. The term “permeation enhancer” is broadly used herein to describe a substance which, when applied to a body surface through which the agent is delivered, enhances its transdermal flux. The mechanism may involve an increase in the permeability of the body surface, a reduction in the degradation of the agent (e.g., degradation by skin enzymes) during transport, or in the case of electrotransport delivery/sampling, a reduction of the electrical resistance of the body surface to the passage of the agent therethrough or, the creation of hydrophilic pathways through the body surface.
There have been many attempts to enhance transdermal flux by mechanically puncturing the skin prior to transdermal drug delivery. See for example U.S. Pat. No. 5,279,544 issued to Gross et al., U.S, Pat. No. 5,250,023 issued to Lee et al., and U.S, Pat. No. 3,964,482 issued to Gerstel et al. These devices utilize tubular or cylindrical structures generally, although Gerstel does disclose the use of other shapes, to pierce the outer layer of the skin. Each of these devices provide manufacturing challenges, resistance to easy penetration of the skin, and/or undesirable irritation of the skin.
As has been discussed, a variety of chemicals and mechanical means have been explored to enhance transdermal flux. However, there is still a need to provide a device suitable for increasing transdermal flux which device penetrates the skin with very little insertion force, is low-cost and which can be manufactured reproducibly (i.e., without significant variation from device to device) in high volume production.
DESCRIPTION OF THE INVENTION
The present invention provides a reproducible, high volume production, low-cost device capable of penetrating the skin easily and suitable for increasing transdermal flux. The invention comprises a plurality of microblades for piercing the skin having a leading edge with a relatively sharp angled first segment which transitions to a relatively gradually angled second segment. The particular microblade geometry allows better penetration of the skin with less “push down” (i.e., penetration and insertion) force required of the user. The first segment forms a relatively small angle with respect to an axis extending along the length of the microblade to provide a very pointed section on the blade that pierces the skin readily. The leading edge then transitions to a second segment which forms a larger angle relative to the axis than the first segment. The second segment provides strength to the overall blade to prevent bending due to the wider blade along that portion compared to the portion along the first segment. The second segment, because of its larger width, also forms longer slits in the skin thereby increasing the size of the transdermal pathways through which agents can be delivered or withdrawn. Together, the sharper blade tip and the relatively stronger blade base, improve the overall penetration characteristics of the microblade and thereby reduce the push down force needed to achieve the desired penetration quality.
The blades typically have a length of less than about 0.5 mm and a width and thickness which is even smaller. In spite of their small size, the microblades can be made with an extremely reproducible size and shape so that the microslits formed by the microblades puncturing the skin also have a very reproducible size and depth. Because the microblades have a small thickness (i.e., small relative to the width and length of the blades), the microblades produce less tissue damage for a given cross-section than a skin piercing microneedle having a circular cross-section. The device of the present invention pierces the stratum corneum of a body surface to form pathways through which a substance (e.g., a drug) can be introduced (i.e., delivery) or through which a substance (e.g., a body electrolyte) can be withdrawn (i.e., sampling).
In one aspect of the invention, the device comprises a sheet having a plurality of openings therethrough, a plurality of microblades integral therewith and extending downward therefrom, at least a portion of the microblades having a leading edge with a first angled segment and contiguous with the first angled segment a second angled segment, the first angled segment being located distally on the microblade and having a first angle relative to an axis along the length of the microblade, the second angled segment having an angle greater relative to the axis than the first angle.
The device of the present invention can be used in connection with drug delivery, body analyte or drug sampling, or both. Delivery devices for use with the present invention include, but are not limited to, electrotransport devices, passive devices, osmotic devices and pressure-driven devices. Sampling devices for use with the present invention include, but are not limited to, “reverse” electrotransport devices such as disclosed in Glikfeld et al., U.S. Pat. No. 5,279,543 and Guy et al., U.S. Pat. No. 5,362,307, passive diffusion devices such as disclosed in Schoendorfer, U.S. Pat. No. 5,438,984, osmotic devices such as disclosed in
Block Barry
Cormier Michel J. N.
Nat Avtar S.
Neukermans Armand P.
ALZA Corporation
Bates Owen J.
Miller D. Byron
Rodriguez Cris L.
Seidel Richard K.
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