US 20050085766 A1
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.
1. An apparatus for applying to a body surface, comprising:
an expandable member having a body surface engaging first portion and a body surface engaging second portion, said body surface engaging first and second portions being adapted to apply a tension of about 0.01 to about 10 M Pa to the body surface when the member is expanded; and
a microprojection member having a plurality of microprotrusions for penetrating the body surface, said plurality of microprotrusions being disposed between said first portion and said second portion of said expandable member.
2. The apparatus of
3. The apparatus of
4. The apparatus of
5. The apparatus of
6. The apparatus of
a retainer that initially holds said body surface engaging first and second portions in a first position; and
a biasing member for urging said body surface engaging first portion away from said body surface engaging second portion when said retainer is removed.
7. The apparatus of
means for holding said expandable member in an expanded state after said member has been expanded.
8. The apparatus of
9. The apparatus of
a first sheet member having a first set of microprotrusions extending outward therefrom, said first sheet member being in communication with said body surface engaging first portion; and
a second sheet member having a second set of microprotrusions extending outward therefrom, said second sheet member being in communication with said body surface second portion, whereby when said expandable member is expanded said first sheet member moves in a direction parallel to said second sheet member and away from said body surface engaging said second portion.
10. The apparatus of
11. The apparatus of
12. A transdermal agent delivery devices comprising:
a skin stretching device for stretching skin by applying a tension of about 0.01 to about 10 M Pa to the skin; and
an agent containing member having an array of microprotrusions, wherein said skin stretching device is configured to stretch the skin of a subject and maintain said skin in a stretched state during penetration of said skin by said microprotrusions.
13. The device of
14. The device of
15. The device of
16. The device of
17. The device of
18. The device of
19. The device of
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.
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 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.
One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface referred to as “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 a different extent. Accordingly, the term “electrotransport” is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent is actually being transported. Electrotransport delivery generally increases agent delivery and reduces polypeptide degradation during transdermal delivery.
Another method of increasing the agent flux involves pre-treating the skin with, or co-delivering with the beneficial agent, a skin permeation enhancer. A permeation enhancer substance, when applied to a body surface through which the agent is delivered, enhances its flux therethrough such as by increasing the permselectivity and/or permeability of the body surface, reducing the electrical resistance of the body surface to the passage of the agent and/or creating hydrophilic pathways through the body surface in the case of transdermal electrotransport delivery, and/or reducing the degradation of the agent.
There also have been many attempts to mechanically penetrate or disrupt the skin in order to enhance the transdermal flux. See for example, U.S. Pat. Nos. 3,814,097 issued to Ganderton, et al., U.S. Pat. No. 5,279,544 issued to Gross, et al., U.S. Pat. No. 5,250,023 issued to Lee, et al., U.S. Pat. No. 3,964,482 issued to Gerstel, et al., Reissue U.S. Pat. No. 25,637 issued to Kravitz, et al., and PCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, and WO 97/48442. These devices use piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin. The piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet. The piercing elements in some of these devices are extremely small, some having dimensions (i.e., a microblade length and width) of only about 25-400 μm and a microblade thickness of only about 5-50 μm. These tiny piercing/cutting elements are meant to make correspondingly small microslits/microcuts in the stratum corneum for enhanced transdermal agent delivery therethrough.
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
The device of the present invention more consistently and reliably penetrates a body surface, e.g., the outermost layer of skin, to enhance agent delivery through 1) greater uniformity of the penetration pattern, 2) deeper penetration with the same size or smaller microprotrusions, and 3) increased size of the resulting pathways. The present invention provides enhanced penetration by controlling the effective mechanical properties of the body surface by reducing the compliance, i.e., extensibility, of the body surface 30. The compliance or extensibility is reduced by applying tension at the application site, i.e., stretching the skin taut, during penetration of the body surface with skin penetrating elements 34 as shown in
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
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:
Iext is the length of a sample of skin in a stretched state; and
Inon-ext is the length of the skin sample in a non-stretched state.
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.
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.
The device of the present invention can be used in connection with agent delivery, and in particular, transdermal drug delivery. Delivery devices for use with the present invention include, but are not limited to, electrotransport devices, passive devices, osmotic devices, and pressure-driven devices.
Many objects and advantages of the present invention will be apparent to those skilled in the art when this specification is read in conjunction with the attached drawings, wherein like reference numerals are applied to like elements, and wherein:
As shown in
The present invention involves stretching a body surface (e.g., skin) just prior to and during piercing with the microprotrusions of the aforementioned size to create a plurality of microcuts/microslits therein. The microcuts/microslits can be formed by any suitable body surface penetrating device as the invention is not limited in this respect except with respect to the size of the microprotrusions. Thus, the present invention can be used with many known skin piercing or skin cutting microprotrusions, for example, those described in U.S. Pat. Nos. 5,279,544; 3,964,482; 5,250,023; Reissue 25,637; 5,312,456 and those disclosed in PCT Publication Nos. WO 97/48440, WO 96/37256, WO 97/03718, WO 98/11937, and WO 98/00193, which are incorporated herein by reference in their entirety. One particularly preferred type of microprotrusion device is shown in
A particularly preferred configuration for the microprotrusion device is illustrated in
In either the
As used herein, the term “stretching” means applying a tension in the range of about 0.01 to about 10 M Pa, and preferably about 0.05 to about 2 M Pa, to the skin at the time of puncturing the skin with the microprotrusions. As used herein, the term “unilateral stretching” means tensioning the skin in one direction. As used herein, the term “bilateral stretching” means tensioning the skin in two directions. As used herein, the term “shear puncturing” means the microprotrusions are moved parallel to the surface of the skin. As used herein, the term “normal puncturing” means the microprotrusions are moved normal to the surface of the skin. As used herein, the term “longitudinal shearing” means shear loading that is oriented parallel to the direction that the skin is stretched. As used herein, the term “transverse shearing” means shear loading that is oriented orthogonal to the direction that the skin is stretched. As used herein, the term “global puncturing” refers to microprotrusions that all move as a single unit rather than relative to one another during insertion. As used herein, the term “local puncturing” refers to microprotrusions which move relative to one another, usually in opposite directions, during insertion.
The device of the present invention is for use in the percutaneous administration of an agent. The terms “substance”, “agent”, and “drug” can be used interchangeably and broadly include physiologically or pharmacologically active substances for producing a localized or systemic effect or effects in mammals, including humans and primates, avians, valuable domestic household, sport, or farm animals, or for administering to laboratory animals such as mice, rats, guinea pigs, and the like.
The major barrier properties of the skin, such as resistance to agent permeation, reside with the outermost layer of the skin, i.e., stratum corneum. The inner division, i.e., the underlying layers, of the epidermis generally comprise three layers commonly identified as stratum granulosum, stratum malpighii, and stratum germinativum. There is essentially little or no resistance to transport or to absorption of an agent through these layers. Therefore, for enhancing transdermal flux the microprotrusions used to create pathways in the body surface in accordance with the present invention need only penetrate through the stratum corneum in order for the agent to be transdermally delivered with little or no resistance through the skin.
The devices shown in
The expandable device 100 shown in
A second embodiment of the invention is illustrated in
A third embodiment of the invention is illustrated in
The fourth embodiment of the invention is illustrated in
In addition to shear puncturing, device 103 provides bi-directional stretching of the skin. The skin is stretched in one direction prior to cartridge housing 44 being inserted and in an orthogonal direction when the cartridge housing 44 is inserted. As shown in
In some embodiments of the sheet member 36, the microprotrusions 34 are angled or slanted in the same direction. With this configuration, the cartridge housing 44 can be slid along the body surface in the direction of the slanted microprotrusions while pressing down on the cartridge housing to facilitate better penetration against the elastic nature of the skin.
As one of ordinary skill in the art will recognize, it is also within the scope of the invention that the cartridge housing 44 could be pressed down normal to the plane of the skin with inclined surfaces and ends as described with respect to devices 100, 101, and 102, which would provide bi-directional stretching. In this way, rather than resulting in global, shear puncture as does device 103, it would result in global, normal puncture.
As an alternative, the portion of device 103 illustrated in
A fifth embodiment of the invention is illustrated in
A sixth embodiment of the invention is illustrated in
A seventh embodiment of the invention is illustrated in
An eighth embodiment of the invention is illustrated in
In the preferred embodiments, the microprotrusions 34 are microprotrusions as shown in
The preferred configurations for the array of microprotrusions and a connecting medium for delivering agents between the reservoir 42 and the body surface are described in detail in WO 97/48440; WO 97/48441; WO 97/48442; and WO 98/28037 which are incorporated herein by reference in their entirety.
The array of microprotrusions 34 in the various embodiments of the present invention may take on different shapes. The present invention can be used with any known delivery device and is not limited to any particular device. It will be appreciated by those working in the field that the present invention can be used in conjunction with a wide variety of electrotransport systems, as the invention is not limited in any way in this regard, see for example electrotransport systems disclosed in U.S. Pat. Nos. 5,147,296; 5,080,646; 5,169,382; 5,423,739; 5,385,543; 5,310,404; and 5,169,383; and PCT Publication No. WO 97/48440, which are incorporated herein by reference in their entirety. Similarly, any known passive transdermal delivery device can be used with the present invention, as the invention is not limited in this regard, see for example passive systems disclosed in U.S. Pat. Nos. 4,379,454; 4,588,580; 4,832,953; 4,698,062; 4,867,982; and 5,268,209; and PCT Publication No. WO 97/48440, which are incorporated herein by reference in their entirety. It will be appreciated by those working in the field that the present invention can also be used in conjunction with a wide variety of osmotic and pressure driven systems, as the invention is not limited to a particular device in this regard, for example see U.S. Pat. Nos. 4,340,480; 4,655,766; 4,753,651; 5,279,544; 4,655,766; 5,242,406; and 4,753,651; which are incorporated herein by reference in their entirety.
To determine the effect of stretching the skin during application of a transdermal delivery device having skin piercing microprotrusions along a skin-contacting surface of the device, the following experiment was performed.
Excised hairless guinea pig skin was pierced, under stretched and unstretched conditions, using a microprotrusion array having a configuration similar to that shown in
Sample 1: 1 kg/cm2 normal pressure was applied manually for 30 seconds, with no skin stretching.
Sample 2: 1 kg/cm2 normal pressure was applied manually for 30 seconds on manually stretched skin.
The microcuts on sample 1 were smaller than those on sample 2. When the methylene blue was allowed to diffuse in via the microcuts, more dye was found in the larger microcuts of sample 2. This is qualitative data based only on the relative sizes of the dye spots.
Skin extensibility was evaluated in humans using a CUTOMETER SEM 575® (COURAGE+KAHZAKA electronic, GmbH, Koln, Germany) which is conventionally used for measuring skin elasticity in dermatoglogical applications. The CUTOMETER probe (a metal cylinder having a length of about 10 cm, an outside diameter of 3 cm and an inside diameter of 6 mm) was applied on the ventral forearm of four female and four male volunteers ages 26 to 42 years to measure skin extensibility (E). The CUTOMETER applies a negative pressure of 0.5 bar through the inner (6 mm diameter) opening of the probe which is pressed against the skin. The negative pressure causes the skin to be drawn into the probe opening. The CUTOMETER measures the distance the skin is drawn into the probe and provides a skin extensibility (E) measurement in units of distance (mm). Skin extensibility was measured in a normal (i.e., non-stretched) condition as well as under bi-directional (
Penetration of the microprotrusion array is dependent on the skin physical properties. Reduction of the skin extensibility by stretching indicates that stretching of the skin facilitates penetration of the microprotrusion array for a given force. In addition, it was discovered that stretching of the skin made extensibility of the skin more uniform from subject to subject. This indicates that skin stretching will result in a more uniform application/penetration of the microprotrusion array.
The drug lisinopril does not penetrate the skin significantly without the use of penetration enhancers or physical disruption of the skin barrier. In this experiment, lisinopril was delivered by passive diffusion through pathways in the skin created by an array of microprotrusions. The purpose of the experiment was to show that stretching the skin prior to pretreatment with the microprotrusion array improved flux of the drug through the skin in vivo.
In one group of 12 hairless guinea pigs the skin of one flank was stretched manually bi-directionally (
A second group of 12 hairless guinea pigs were treated in the same way, except that the skin was not stretched. At 12, 24, and 48 hours after application four systems from each group were removed and residual drug was washed from the skin. The amount of drug penetrated during these time intervals was determined by measuring urinary excretion of tritium (previous studies has shown that in hairless guinea pigs 80% of the tritium derived from 3H-lisinopril injected intravenously is excreted in urine). The results shown in
This study examined the effect of skin stretching applied before and maintained during application of a microprotrusion array on the electrically assisted insulin flux in the hairless guinea pig.
Hairless guinea pigs were divided randomly into two groups of four animals. One group of animals received the microprotrusion array delivery system without skin stretching, and the other, received the microprotrusion blade array with skin stretching during application. In the group undergoing skin stretching, the skin of one flank was stretched manually bi-directionally (
A hydrogel containing Humulin R-500 (Eli Lilly, Indianapolis, Ind.) supplemented with a final concentration of 25 mM L-histidine (base) and 2% (w/v) hydroxylethyl cellulose, was dispensed into the drug compartment. The remainder of the iontophoretic system was added to this construction. The drug-containing formulation was separated from the cathode electrode by a Nafion ion exchange membrane. A gel containing 0.15M sodium chloride was placed between the cathode and the ionic exchange membrane. The system also comprised an anode compartment which comprised a skin-contacting gel containing a saline hydrogel and an anode electrode. The current was preset to 100 μA/cm2. The system was maintained on the animal skin for 2 hours. Blood samples were also collected at 0.5, 1, 2, 3, and 4 hours after system removal. Plasma was then prepared from these blood samples and insulin was analyzed by radioimmunoassay.
The results shown in
This experiment measured the effect of skin stretching on microprotrusion penetration depth using excised hairless guinea pig skin. Two hairless guinea pigs were used in the experiment. Before sacrifice, the skin extensibility (E) of each of the animals was measured using the CUTOMETER described in Example 2. A CUTOMETER probe having an inside diameter of 8 mm was used to measure skin extensibility in this experiment. Six measurements were taken on each side of the animals; three in a natural (i.e., non-stretched) condition and three using manual bi-directional (
Following these measurements, the animals were sacrificed and skinned from the neck through hind leg region using a scalpel blade. Excess fat under the skin was then removed. The skins were then cleaned with isopropyl alcohol swabs and dried with gauze. The excised skins were then placed over a thin silicone sheet (thickness of 0.3 cm) mounted over a thin piece (thickness of 0.3 cm) of cork board. The excised skins were placed over the silicone and stapled along their perimeter to secure the skins thereto. Skin extensibility measurements were taken with the CUTOMETER and the skin stretch was adjusted (i.e., by removing staples and then restapling) in order to match the extensibility measurements of the live animals. Once the mounted skins had extensibility measurements which matched those of the live animal, the skin tension was assumed to be the same as that achieved through bi-directional stretching of the live animal's skin, and experiments were conducted to measure microprotrusion penetration depth. The microprotrusions used in the experiment were in the form of the metal sheet having a thickness of 0.025 mm (1 mil) having a multiplicity of openings (190 openings/cm2), each opening having one trapezoidally shaped microblade bent at an angle of about 90
After impact penetration by the microprotrusion array, the skin site was rubbed with india ink both horizontally and vertically for about 15 seconds. Thereafter, the site was cleaned with gauze and water until the surface ink was removed. Each treatment site was then labeled and photographed in order to determine the amount of microslits across the impacted site and the number of microslits/cm2.
The skin samples were then wrapped in foil and sealed in a plastic bag and placed in a freezer overnight. Upon removal from the freezer, three 6 mm cryotomed biopsies were taken from each skin site. The slices were placed on a glass slide in order of increasing depth. When the cryotoming was completed, the india ink stains in each slice were counted at each depth and recorded to determine the penetration of the projections at each depth. The photographs taken prior to cryotoming were used to count the number of penetrations at the surface of each of the sites. For each biopsy, the number of projections that penetrated to, but not yet beyond, each slice was calculated. This data was used to determine mean microprotrusion penetration depths, which are as follows:
It will be appreciated by those of ordinary skill in the art that the invention can be embodied in other specific forms without departing from the spirit or essential character thereof. The presently disclosed embodiments are therefore considered in all respects to be illustrative and not restrictive. The scope of the invention as indicated by the appended claims rather than the foregoing description, and all changes which come within the meaning and range of equivalence thereof are intended to be embraced therein.