Device and method for enhancing skin piercing by microprotrusions

Abstract

A device and method for enhancing skin piercing by microprotrusions involves pre-stretching the skin to enhance pathway formation when the microprotrusions are pressed into the skin. An expandable device includes skin engaging opposite ends that contact the skin surface so that when the device is expanded the skin is stretched. The skin is placed under a tension of about 0.01 to about 10 megapascals, preferably about 0.05 to 2 megapascals. The device has a plurality of microprotrusions which penetrate the skin while the skin is being stretched by the expanded device. Another stretching device employs suction for skin stretching.

Description

TECHNICAL FIELD [0001] The present invention relates to transdermal agent delivery and more particularly, to the transdermal delivery of macromolecular agents such as polypeptides, proteins, oligonucleotides and polysaccharides. The present invention relates to devices which have microprotrusions to pierce the outermost layer of a body surface (e.g., the skin) to enhance the transdermal flux of the agents during transdermal delivery. BACKGROUND ART [0002] Interest in the percutaneous or transdermal delivery of peptides, proteins, and other macromolecules, such as oligonucleotides, 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 low transdermal pe...

AI Technical Summary

Benefits of technology

[0008] The device of the present invention stretches the patient's skin during penetration by a plurality of microprotrusions. As used herein, the term “microprotrusions” refers to very tiny skin piercing elements, typically having a length of less than 500 μm, a width of less than 400 μm and a thickness of 5 to 100 μm which make correspondingly sized microcuts / microslits in the skin. Upon piercing through the outermost layer (i.e., the stratum corneum) of the skin, the microprotrusions form pathways as shown in FIGS. 3 and 4 through which an agent such as a drug can be introduced, i.e., transdermally delivered. A principal advantage of the present invention is that the device ensures uniform penetration, i.e., generates the same size and depth pathways, by the microprotrusions across the device. Furthermore, the present invention reproducibly provides uniformity in penetration from patient to patient and can form deeper penetrations with shorter microprotrusions.

[0009] The device of the present invention uses stretching elements which engage the surface of the skin, such as with adhesive, and create opposing forces across the surface of the skin surface so as to create tension at the skin surface between the skin stretching elements. When piercing the skin with very tiny microprotrusions, the degree of tension under which the skin is placed becomes much more critical compared to skin piercing using substantially larger skin piercing elements such as blood drawing lancets. In accordance with the present invention using microprotrusion piercing, the skin is placed under a tension in the range of about 0.01 to about 10 M Pa, and preferably in the range of about 0.05 to about 2 M Pa (M Pa=megapascal=1×106 pascals). Thus, the skin stretching / tensioning devices according to the present invention apply a predetermined amount of tension (i.e., stress) in the range from about 0.01 to about 10 M Pa, and preferably in the range of about 0.05 to about 2 M Pa. The amount of skin strain resulting from a given tension varies between individuals depending upon skin characteristics, such as the age of the patient, the location on the patient's body and the tensioning direction. Therefore, in order to adapt to individual characteristics and improve penetration, the skin tensioning devices according to the present invention preferably are designed to provide a given tension (stress) rather than a given strain. In general, for these stress or tension ranges, the applied skin strain is within about 5 to 60% and most preferably within about 10 to 50%. Strain is the amount of skin stretch per unit length of skin and is defined as the change in length of skin in an extended or stretched state divided by the length of skin in a non-stretched state. The strain can be expressed mathematically by the following equation: Strain=(Iedt−Inon-ext)+In-ext wherein:

[0010] Iext is the length of a sample of skin in a stretched state; and

[0011] Inon-ext is the length of the skin sample in a non-stretched state.

[0012] With the skin in tension, the skin is less compliant and less extensible, resulting in the microprotrusions being able to pierce the outermost layer of the skin without the skin conforming around or giving way to the microprotrusions so easily. The stretched skin allows nearly complete penetration by all of the microprotrusions, so as to produce a substantial number of agent pathways and electrical continuity (if electrotransport is used) with the skin for continued and reproducible agent flux through the skin. With the skin at the site of application being held taut by the stretching elements the surface of the skin itself is now exerting more resistance to the applied pressure by the points of the microprotrusions. This allows for more reproducible penetration from patient to patient, or from one site to another on a patient, by making the underlying characteristics of the tissue layers under the stratum corneum less influential on penetration as the surface of the skin is exerting resistance to the applied pressure.

[0013] In one aspect of the invention, the apparatus comprises an expandable device with skin engaging portions which in use stretches the patient's skin, and a skin penetrating device having a plurality of microprotrusions adapted to pierce the stratum corneum prior to transdermal agent delivery therethrough. One example of a suitable skin penetrating device includes a relatively thin, flexible sheet, which in use is adapted to be placed in substantially parallel relation with the body surface to be pierced. The sheet has a plurality of microprotrusions extending perpendicularly from a body proximal side of the sheet and at least one opening therethrough, which allows the agent to pass between a reservoir associated with the sheet (and typically positioned on the body distal surface of the sheet) and the holes or pathways pierced in the outermost layer of the body surface by the microprotrusions.

Problems solved by technology

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 low transdermal permeability coefficient of macromolecules and 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 transdermal flux of many low molecular weight compounds is too limited to be therapeutically effective.

A limitation on devices having such tiny skin penetrating elements is that the elastic properties of the patient's skin 30 allow the skin to conform around the individual skin penetrating elements 32 significantly before those elements actually breach the skin as shown in FIG. 1.

In addition, the tissue layers under the stratum corneum can cause uneven distribution of the total force applied by allowing more conformance around some microprotrusions than others, resulting in several different local pressures across the site.

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