WO2002030506A2

WO2002030506A2 - Transdermal method

Info

Publication number: WO2002030506A2
Application number: PCT/IL2001/000941
Authority: WO
Inventors: Amiram Carmon; Benyamina Rosenberg-Hagen; Eliezer Rosenmann
Original assignee: Ink Jet Technology Ltd.
Priority date: 2000-10-12
Filing date: 2001-10-11
Publication date: 2002-04-18
Also published as: AU2002210881A1; WO2002030506A3

Abstract

A method for transport through a skin surface comprising (i) applying a microdosing device to the skin surface, (ii) ejecting from the device a keratolytic agent onto the skin surface thereby forming at least one blister containing interstitial fluid, and (iii) transporting an active agent into the blister, transporting interstitial fluid from the blister, or both. The keratolytic agent is not cantharidine. Also disclosed is a microdosing device comprising at least two sets of conduits, a first set capable of ejecting an keratolytic agent and a second set capable of transporting a liquid.

Description

TRANSDERMAL METHOD

FIELD OF THE INVENTION

This invention relates to a method and device for transdermal drug delivery and body fluid sampling.

BACKGROUND OF THE INVENTION Transdermal drug delivery has become very prevalent. The list of drugs delivered by this method is quite long and includes estrogens, testosterone, Fentanyl, Clonidine, Nitrates and Nicotine.

In structure the skin is composed of two distinct layers. The outer layer, called the epidermis or cuticle, is several cells thick and has an external, horny layer of dead cells, called the stratum corneum, that is constantly shed from the surface and replaced from below by a basal layer of cells, the stratum germinativum. The inner layer, called the corium or dermis, is composed of a network of collagen and elastic fibers, blood vessels, nerves, fat lobules, and the bases of hair follicles and sweat glands. The epidermis is an active living structure. The stratum germinativum is composed of continuously dividing and thus multiplying cells that push the cells above them to the outside. The more superficial the cells, their aging is more marked. The layers above the stratum germinativum are the stratum granulosum, stratum spinosum and stratum lucidum, where the already aged cells are flattened and dehydrated before they die and become the components of the stratum corneum. The dead cells are known as karyocytes, which are filled with keratin (the same substance present in nails, hairs and horns). Eventually these karyocytes will be shed and will give place to more recently dying cells. The continuous shedding of the skin help to keep the outer, exposed skin surface in good shape, as the dead karyocytes are not strongly attached to each other.

As the stratum corneum is a formidable barrier that blocks direct access to the bodily fluids below it, the efficacy of transdermal drug delivery is low. This layer of the skin is best viewed as a membrane made of tiles only partially cemented to each other by desmosomes made of proteins and fats. There are sufficient gaps between the tiles that allow liquids to penetrate, albeit slowly, between the cracks into the body. The larger the molecules, the less they penetrate through the small cracks. In light of this "tile roof like structure many attempts were made to introduce chemical substances that will allow more active passage between the dead cells into the spaces between the living cells, in the same way that lubricant enhance passages of objects in narrow passages.

The rationale of getting drugs below dead cells into layers with living ones is that the cells in the body are not completely glued to each other and there are fluid-filled spaces around them commonly referred as the "interstitial space". This space is an extension of the blood and lymph system in the sense that it allows the passage of nutrients and oxygen from the blood into the cells, and also allows uptake of waste and C0₂ from the cells into the blood stream to be eliminated from the body through the lungs and kidney. Thus if drugs can reach the interstitial space in a given location they will eventually reach parts of the body and thus their target.

The transdermal drug delivery technology has both advantages as well as disadvantages. On the positive side is the noninvasive nature of the method, as drugs are diffused from a reservoir placed on the skin into the body. On the negative side is the slow rate of the delivery and the inability to use drugs having large-sized molecules. For example, in order to reach a diffusion of 200 micrograms per hour of Fentanyl, a pain relieving opioid with rather modest molecular size, the contacting part of the reservoir through which diffusion occurs must be at least be 40 square centimeters. As for molecular size, drugs with large molecular size, such as insulin, cannot pass through the skin. Theoretically, the best way to overcome the barrier effect of the stratum corneum should be to dispose of the stratum corneum. Short of denuding the skin (a process having dire consequences as seen in burns), a more viable alternative of locally limited penetration was devised. According to this rational, since the penetration is only into the epidermis, a layer devoid of nerve endings, the patient would not feel it and yet drugs could be inserted into the interstitial spaces.

Thus, numerous means and methods have been devised in order to overcome the barrier with a minimum of pain.

Some methods use superficial mechanical penetration and disruption of the upper layers of the epidermis.

US Patent No. 3,814,097 discloses a dressing for administering a drug through the skin of a host. The dressing comprises a reservoir for the drug and, located between the reservoir and the skin of the host when the dressing is in use, a pad provided with tiny spikes. These tiny spikes augment the absorption of the drug without causing irritation.

US Patent No. 3,964,482 discloses a drug delivery device for percutaneously administering a drug. The device comprises a plurality of projections and a drug reservoir containing a drug. The projections extend from the reservoir and are adapted for penetrating the stratum corneum for percutaneously administering a drug from the reservoir to produce a local or systemic physiological or pharmacological effect.

U.S. Patent No. 6,050,988 discloses a device comprising a sheet member having a plurality of microprotrusions extending from a bottom edge for penetrating the skin of a patient. The sheet member when in use is oriented in an approximately perpendicular relation to the patient's skin.

WO 97/48440 discloses a percutaneous agent delivery or sampling device.

The device comprises a sheet having a plurality of microblades for piercing and anchoring to the skin for increasing transdermal flux of an agent and for improving the attachment of the device to the skin. The device further comprises a sheet having at least one opening therethrough and a plurality of blades extending downward therefrom, and an anchoring means for anchoring the device to the body surface.

As the mechanical disruption is not always sufficient to allow rapid introduction of suitable amounts of drugs, it is sometimes assisted by chemical/electrical/gas power means.

U.S. Patent No. 5,279,544 discloses a transdermal drug delivery device which includes a liquid reservoir for a liquid drug to be delivered, and a drug delivery body. The delivery body includes a plurality of tubular elements extending through the body, each having an inlet end communicating with the liquid reservoir, and an outlet end engageable with the subject's skin to conduct the liquid drug directly to the subject's skin. The device is useful in delivering the drug by an electrically-induced mass transfer phenomenon, such as iontophoresis or electrophoresis.

U.S. Patent No. 6,009,345 discloses an apparatus for transdermal molecular delivery. The apparatus comprises a first electrode assembly having an anode and a cathode in closely spaced relation for engaging the stratum corneum through which to apply an electric field, a first power supply including a first circuit connected to the first electrode assembly for applying a pulsed electric field of sufficient amplitude to induce pores in the stratum corneum. It also comprises a second electrode assembly spaced from the first electrode assembly and comprising at least one of an anode and a cathode, a second power supply including a second circuit connected to the first electrode assembly and the second electrode assembly for applying a low voltage continuous electric field of a preselected polarity and sufficient amplitude to induce migration of molecules through pores in the stratum corneum.

U.S. Patent No. 5,250,023 discloses a method that combines mass transfer with mechanical disruption of the epidermis. This method involves contacting and ionizing a protein or peptide drug immersed in hydrophilic polymer with ionizing solvent composition, and forming the drug pathway on epidermis by plural skin needles or treating the skin by a razor. The above ionized drug is then transferred into the skin by electric force.

Indeed, Elan Corporation of Ireland and the USA introduced very recently a transdermal drug delivery device, MediPad, that is equipped with tiny spikes, but in addition it has a gas canister that propels the drug under strong pressure into the epidermis.

In addition to the stratum corneum being a barrier to drug delivery from the outside, it is also a barrier to easily obtaining body fluids for analysis, as it virtually limits seeping of the interstitial fluids into the surroundings. Thus, some techniques that evolved around microporation, use miniature breaks in the stratum corneum as a venue for collecting bodily fluids for chemical analysis.

U.S. Patent No. 5,885,211 discloses a method of enhancing the permeability of the skin to an analyte for diagnostic purposes or to a drug for therapeutic purposes. The method utilizes microporation and optionally sonic energy and a chemical enhancer. If selected, the sonic energy may be modulated by means of frequency modulation, amplitude modulation, phase modulation, and/or combinations thereof. Microporation is accomplished by (a) ablating the stratum corneum by localized rapid heating of water such that such water is vaporized, thus eroding the cells; (b) puncturing the stratum corneum with a micro-lancet calibrated to form a micropore of up to about 1000 μm in diameter; (c) ablating the stratum corneum by focusing a tightly focused beam of sonic energy onto the stratum corneum; (d) hydraulically puncturing the stratum corneum with a high pressure jet of fluid to form a micropore of up to about 1000 μm in diameter, or (e) puncturing the stratum corneum with short pulses of electricity to form a micropore of up to about 1000 μm in diameter. A dye with an absorption maximum matched to the wavelength of a pulsed light source can be absorbed into the stratum corneum to concentrate the energy of the pulsed light source and aid in ablation of the stratum corneum. Alternatively, a hot wire can be caused to contact the stratum corneum.

For those familiar with the art it will be clear that the amount of interstitial fluid attainable through micropores is minuscule, and therefore is difficult to collect and may not be sufficient for some assay methods. Therefore work has been done to significantly increase the amount of accessible interstitial fluid, mostly by creating the well-known phenomenon of "blisters" where large amount of interstitial fluid in the form of exudate becomes available. A mechanical procedure where strong vacuum is applied to the skin for long periods of time can also result in subepidermal blisters which are filled with interstitial fluid. Such a technique is generally employed in pharmacological studies and is not deemed suitable for clinical usage.

In contrast to the delicate micropores described above, U.S. Patent No 5,441,490 is based on drastic removal not only of the stratum corneum but of all the epidermis. This patent discloses an apparatus for removing a small area of epidermis from the skin to expose an intact area of dermis and subsequently deliver a liquid in contact with the exposed dermis. This method of delivery allows the rate of absorption of substances into the body to be enhanced by removal of the epidermis. A preferred embodiment removes the epidermis by forming a suction blister, the apparatus having a housing attached to the skin adhesively to define a chamber in which suction is applied. Suction is applied to the chamber without connection to an external source of suction by means of an evacuated cell separated from the chamber by a disruptable membrane. A tubular member is then actuated to rupture the membrane, disrupt the blister and deliver liquid to the chamber in successive stages of operation of the apparatus.

A technique that draws interstitial fluid from blisters for testing purposes is well known and had been widely used. Cantharidine, a toxin excreted by the Blister Beetle can, when applied to the skin, cause blisters which are filled with exudate constituting mostly of interstitial fluid. Brunner, et al. Br. J. Clin. Pharmacol. (1988) 46:425-431, describes a skin blister fluid sampling method for the direct assessment of peripheral pharmacokinetics in humans. The skin blisters are cantharidine-induced.

However, due to its toxicity, the use of Cantharidine has in general been discontinued, at least in the USA. Several companies produce and market transdermal drug delivery "patches", such as Alza Corp (Utah, USA), Elan (Dublin, Ireland) and LTS Lohmann GmbH (Germany).

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for transdermal delivery of drugs.

It is another object of the invention to provide a method of transdermal sampling of bodily fluids.

It is a still further object of the invention to provide a device for use in the method of the invention.

In one aspect of the invention, there is provided a method for fluid transport through a skin surface comprising:

(i) applying a microdosing device to the skin surface, the device comprising a plurality of conduits, (ii) ejecting from one or more of the conduits a keratolytic agent (KA) onto the skin surface thereby forming at least one blister containing interstitial fluid, and (iii) transporting an active agent into the blister, transporting interstitial fluid from the blister, or both, through one or more of the conduits, wherein the keratolytic agent is not cantharidine.

The present invention uses a rationale diametrically opposed to that of the prior art. Instead of trying to reach the interstitial fluid from the outside, so as to introduce drugs through it, the present invention is based on a procedure that makes the fluid more accessible and then introduces the drug into this fluid. As the interstitial fluid excreted according to the invention still communicates freely through the interstitial spaces with other bodily fluids such as blood and lymph, drugs introduced directly into it will rapidly reach the rest of the body and thus the target organs. Such an approach has other important benefits, namely the ability to draw bodily fluid for testing. When both testing and delivery are possible at the same location and concomitantly, a "servo" drug delivery system can be created. One example is in the case of diabetes. Glucose can be measured from the interstitial fluid (with 95% accuracy in relation to its level in the blood) and insulin in appropriate amounts can then be delivered into the same interstitial fluid pool.

This aspect of the invention utilizes very superficial intraepidermal blisters caused by application of KA to the skin, which are controllable in size and location and can be minuscule, as well as being transient. Once created, they can serve for both collecting interstitial fluid for testing as well as for drug delivery. As the drug is introduced into a fluid pool, the amount of pressure needed is very small and the flow is simplified.

The term "active agent' relates to any substance which is desired to be delivered to the body transderaially. Generally, these will be medicaments, drugs or other chemicals. In the present specification, the term "drug" is often used interchangeably with "active agent".

The keratolytic agent (KA) used in the method of the invention is any agent, with the exception of cantharidine, capable of dissolving keratin in the cells of the stratum corneum, thereby forming a blister. Preferably, the KA is a weak acid, more preferably a weak organic acid. Examples of KA include but are not limited to various alpha hydroxy acids and other chemical agents such as glycolic, lactic, pyruvic, trichloroacetic, phenolic, and salicyclic acids. Many of these acids are materials used in cosmetic creams to remove the uppermost layer of dead cells, "rejuvenating" the skin by making its appearance smoother. The same materials, but in higher concentrations are used in dermatological plastic surgery for peeling completely the stratum corneum, and in prolonged applications can remove completely the epidermis.

A well known phenomenon in "chemical peeling" of the skin is that these acids, in sufficient concentrations, cause tiny blisters to appear on the skin giving it "frost like" appearance. Even if the appearance to the normal eye is of intact skin, histological sections show that many materials cause separation of the stratum corneum from the underlying skin and collection of fluid under it. In the cases where the materials are at concentrations that cause blisters to appear to the naked eye, histological sections demonstrate large blisters with a depth of few hundred microns.

The phenomenon is evident several minutes after the application of the acids, but can be short lived at certain concentrations of the above mentioned materials. It is noticed in the living skin but is rare in in vitro preparations. Clinically, the application of the acids can result in tingling or slight burn sensation, which depends on the size of the area involved.

The present invention utilizes the same materials in a solution form but applies them to the skin by a microdosing device that is similar to ink jet print head. Such heads can eject very small droplets in the order of few picoliters. Thus, there is a tight control of the amount of the ejected solution. As the number of drops ejected determine the total quantity of the applied solution, the desired amount can be predeteermined. Furthermore as the size of the droplets is small and they are ejected in the same place, it is possible to limit the application of the solution to very tiny spots much less than a millimeter in diameter. The results are very tiny circumscribed blisters. Once a blister is created it can be used either to draw out interstitial fluid or to inject drugs into it. As ink jet like mechanisms are used with multiple ejectors it is possible to create simultaneously a sufficient number of the blisters.

In a second aspect of the invention, there is provided a microdosing device comprising at least two sets of conduits, a first set capable of ejecting an keratolytic agent and a second set capable of transporting a liquid.

In a preferred embodiment, each of the first set of conduits comprises a firing chamber terminating in a nozzle which allows a highly controlled application of KA by using a specially designed ejecting mechanism, such as that based on the technology of piezo driven drop-on-demand ink jet print heads. For example, a liquid is contained in extremely small chambers, and a piezo element deflects a flexible membrane sealing part of the chamber. This deflection, which is instantaneous, is achieved by applying a very brief voltage pulse to the piezo element. The sudden deflection creates an acoustic wave inside the liquid containing chamber. The chamber has an opening in the form of a tiny nozzle, and the acoustic wave force out a tiny droplet of liquid.

This technology is well known to the average skilled person of the art, and it is not necessary to discuss it here in detail.

Examples of important parameters include: Droplets may be as small as 3 picoliters;

Drop velocity may be in the range of 8-12 m/sec, preferably 10 m/sec, allowing very precise placement across short distances;

Rate of ejection of droplets may be over 25 kHz;

Viscosity of ejected liquid can be as high as 30 centiPoise, as reported by Aprion Digital of Israel, a company that designs and manufactures ink jet heads and systems.

Each of the second set of conduits in this preferred embodiment terminates in short rigid microtubes, preferably, but not limited to, 100 micron stainless steel tubes, such as are manufactured by Ohbakiko Company of Fujinomya, Japan. Such tubes preferably, but not necessarily, are cut at one side at a 45-60° angle. These tubes, which are capable of piercing the uppermost layers of the epidermis, such as the stratum corneum, protrude from the device to a greater degree than the conduits of the first set. They may be connected to a fluid reservoir containing medications or other active agents. These conduits are in turn discretely connected to very thin flexible tubes, each flexible tube being actuated by a piezomotor that rolls along the flexible tube, thereby applying pressure on it. By changing the direction of movement it is possible to eject liquid (e.g. drug) into the blister or to withdraw fluid from the blister. - l i ¬

lt is clear, that at least in this embodiment, the ejection tubes and withdrawing tubes belong to separate systems, and therefore are connected to different reservoirs. However, the ejection nozzles and transporting microtubes are in close proximity one to the other, so that the transporting microtubes can penetrate the blisters formed by the ejection nozzles.

In a further preferred embodiment, two sets of ejecting nozzles which are connected to piezo driven chambers as described above, are used. The two sets may be arranged in two lines with the pairs of nozzles, one belonging to one set, and the other belonging to the other set, placed in closest proximity to each other. Those familiar with the art of ink jet printing heads will recognize that an inter-pair nozzle distance of 1/150 or 1/300 inch is feasible.

While in standard ink jet heads all nozzles deliver the same liquid from a common reservoir through feeding channels, in the present invention the two distinct sets are fed from different feeding channels, each of such feeding channels being connected to a different reservoir. Thus, in each pair, one nozzle ejects one type of liquid, while the second member of the pair ejects another type of liquid, but with the different ejected drops placed in an overlapping manner. This overlapping can be enhanced by having nozzles drilled in a slightly angular direction, and by having large enough drops ejected. In this embodiment it is therefore possible to eject a strong KA that will not only cause a blister to appear, but also weaken considerably or ablate completely the stratum corneum. This will enable the liquid ejected from the other nozzle in the pair, for example a drug, to easily diffuse or penetrate into the blisters or to the underlying epidermal layers without mechanical penetration. As the operation of the piezo elements is controlled electronically, those familiar with the art can see that the timing and rate of ejections as well as amount of ejected fluid can be totally independent for each member of the pair.

In addition to the "matching pairs" design where one member of the pair ejects KA and the other a drug, additional independent jetting heads can be incorporated into the device. Such additional jetting heads may be used for other functions, such as flushing out debris of the stratum corneum dissolve by the KA, and neutralizing the KA by a base liquid. Such flushing droplets do not necessarily have to fall precisely above the blister, but rather wet a larger area around it, in order to literally wash away the undesired substances. Those familiar with the art will realize that a single device can incorporate more than one set of two jetting systems, thus allowing dispensing of several drugs within the same device.

In the same manner more than one set of flushing/neutralizing secondary jetting heads can be incorporated into the device, thus enabling the addition of chemical enhancers (for example, dimethyl sulfoxide) that will facilitate drug transport into the skin.

BRIEF DESCRIPTION OF THE DRAWINGS:

In order to understand the invention and to see how it may be carried out in practice, a preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Fig. 1 is a schematic side sectional view of the skin containing a blister;

Fig. 2. is a sectional view of one pair of conduits of one embodiment of a microdosing device according to the invention;

Fig. 3 is a schematic sectional view of one embodiment of a portion of a microdosing device according to the invention; and

Fig. 4 is a schematic view from below of pairs of nozzles according to a preferred embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A schematic illustration of a skin blister formed by one embodiment of the method of the invention is shown in Fig. 1. The skin 2 comprises an upper layer, the epidermis 4, and the lower dermis 6 layer. The upper layer of the epidermis 4 is the stratum corneum 8. A blister 10 forms under one of the upper layers of the epidermis such as the stratum corneum or stratum lucidium, which is just below the stratum corneum. The blister is intraepidermal, that is, it forms within the epidermal layer, and is filled with interstitial fluid 12.

A portion of a microdosing device according to the invention is depicted in Fig. 2. The device comprises a pair 14 of conduits comprising an ejecting conduit 16 and a transporting conduit 18.

The ejecting conduit 16 is made up of a chamber 20 terminating in a nozzle 22, and is covered by a deflection plate 24 on which a piezo element 26 is attached. The chamber contains a solution of KA, and is connected to a liquid supply receptacle (not shown) for replenishing. The nozzle 22 is positioned a small distance above the skin. When an electric pulse is applied to the piezo element 26 it will contract and cause deflection plate 24 to bend and send an acoustic wave through the liquid in the chamber 20 toward nozzle 22. A tiny droplet of the liquid inside the chamber 20 is then ejected from the nozzle onto the skin surface. The fluid is replenished from the liquid supply receptacle by the capillary force at the nozzle.

Adjacent to the ejecting conduit 16 is the transporting conduit 18 terminating in a rigid microtube 28. The microtube 28 of the transporting conduit protrudes to a greater degree than the level of the nozzle 22 of the ejecting tube, e.g. a fraction of a millimeter, thus allowing the transporting conduit to penetrate the blister formed under the ejecting conduit when pushed toward it. The penetration is of sufficient length to penetrate the blister but not the underlying epidermis. Preferably, the distal end 28 of the transporting conduit 18 will be sharp in order to facilitate penetration. Once the distal end of the conduit has penetrated the blister, it can be used to either deliver a medicament into the interstitial fluid in the blister, or extract a sample of the interstitial fluid for testing.

An example of the operation of the microdosing device according to this embodiment is as follows. The device, comprising a plurality of ejecting tubes and rigid transporting tubes incorporated into a flexible thin pad, is placed over the skin. An electric current of a desired number of pulses actuates the piezo resulting in ejection of KA onto the skin. Within a brief, predetermined period of time for allowing the blisters to appear, e.g. a few minutes, the pad is mechanically pushed down through the upper surface of the skin, the rigid transporting microtubes thereby penetrating into the blisters.

Fig. 3 shows how a sample may be drawn out of a blister 30, formed by the application of a keratolytic agent, or a medicament delivered thereto using the method and device of the invention. The microdosing device 32 comprises a set of transporting conduits 18 which function either in sampling or delivery, a first container 34 and a second container 36 in fluid communication therewith through a flexible tube 38, and a pressing means 40 such as a gear wheel which is moved along the flexible tube 38 by a motor (not shown), preferably a small piezo motor controlled by a microprocessor. The pressing means acts as a pulsatile pump, with the direction of movement of the pressing means 40 determining whether the device delivers or removes fluid from the blister. The second container 36 may serve either as a reservoir in the case of medicament delivery or for collecting the extracted interstitial liquid from the blisters in the case of sampling.

The positioning of the conduits in the microdosing device may be understood with reference to Fig. 4. The device comprises at least two sets of conduits, a first set 50 capable of ejecting an keratolytic agent and a second set 52 capable of transporting a liquid. The nozzles 54 of the conduits of the first set 50 are positioned adjacent to the corresponding microtubes 56 of the conduits of the second set 52, thereby forming pairs of conduits. The second set of conduits may be used either to deliver a medicament or other active agent, or to sample the interstitial fluid. The proximity of the tubes of each pair allows the transporting microtubes to penetrate the blister formed by the ejecting nozzles. In a further embodiment, the device comprises one set of ejecting nozzles and two sets of transporting tubes, one set for sampling and one set for delivering. In this manner, the amount of active agent delivered may be determined in real time on the basis of the sample taken. For example, glucose can be measured from the interstitial fluid (with 95% accuracy in relation to its level in the blood) and insulin in appropriate amounts can then be delivered into the same interstitial fluid pool.

Claims

CLAIMS:

1. A method for fluid transport through a skin surface comprising:

(i) applying a microdosing device to the skin surface, said device comprising a plurality of conduits, (ii) ejecting from one or more of said conduits a keratolytic agent (KA) onto the skin surface thereby forming at least one blister containing interstitial fluid, and (iii) transporting an active agent into said blister, transporting interstitial fluid from said blister, or both, through one or more of said conduits, wherein said KA is not cantharidine.

2. A method according to Claim 1 wherein said KA is a weak acid.

3. A method according to Claim 2 wherein said weak acid is a weak organic acid.

4. A method according to Claim 3 wherein said weak organic acid is one or more acids selected from the group consisting of glycolic, lactic, pyruvic, trichloroacetic, phenolic, salicyclic and α-hydroxy acids.

5. A method according to Claim 1 wherein said blister is intraepidermal.

6. A method according to Claim 1 wherein said microdosing device comprises at least two sets of conduits, a first set ejecting said KA and a second set for transporting fluid into and from the blisters.

7. A method according to Claim 6 wherein the conduits of said first set terminate in a nozzle and the conduits of said second set terminate in a microtube.

8. A method according to Claim 6 wherein the flow of liquid through said conduits is controlled by a microprocessor-controlled pulsatile pump. 9. A method according to Claim 6 wherein the conduits of said second set protrude from the device to a greater degree than the conduits of said first set. 10. A method according to Claim 6 wherein each conduit of said first set is positioned in proximity to a corresponding conduit in said second set. - lo ¬

ll. A method according to Claim 1 wherein said device delivers a medicament into said blister.

12. A method according to Claim 1 wherein said device extracts a sample of said interstitial fluid from said blister.

5 13. A microdosing device comprising at least two sets of conduits, a first set capable of ejecting an keratolytic agent and a second set capable of transporting a liquid.

14. A microdosing device according to Claim 13 wherein each conduit of said first set is positioned adjacent to a corresponding conduit in said second set. 10 15. A microdosing device according to Claim 13 wherein the flow of liquid through said conduits is controlled by a microprocessor-controlled pulsatile pump.