WO2001022881A1

WO2001022881A1 - System for transdermally obtaining body fluids

Info

Publication number: WO2001022881A1
Application number: PCT/EP2000/009175
Authority: WO
Inventors: Matthias Essenpreis; Dirk Boecker
Original assignee: Roche Diagnostics Gmbh
Priority date: 1999-09-25
Filing date: 2000-09-20
Publication date: 2001-04-05
Also published as: WO2001022881A8; EP1220641A1; DE19946059A1

Abstract

The invention relates to a system for transdermally obtaining body fluids to determine at least one analyte. The inventive system comprises a device for transdermally applying at least one particle. Said device is provided with an acceleration device that accelerates the at least one particle to a speed that allows the particle to penetrate a skin area right to the epidermis or dermis and with a release mechanism for releasing the acceleration device and a reservoir for the at least one particle. The particles used in the inventive system are preferably of the kind to be absorbed by the body.

Description

System for the transdermal production of body fluid

The present invention relates to a system for obtaining body fluid through the skin surface in order to determine one or more analytes in the body fluid thus obtained. To obtain the body fluid, a skin area is bombarded with particles so that they penetrate into the epidermis or the dermis. The particles used in the system according to the invention preferably contain no fraction of the analytes to be determined. to avoid falsifying the analysis. Furthermore, the particles are preferably such that they can be resorbed by the epidermis or dermis.

The present invention is in the field of systems and devices for removing body fluids from living beings. Such an extraction is carried out millions of times around the world today to enable medical diagnoses. This area of technology is essentially divided into two. In the first area, amounts of fluid in the range of a few milliliters are withdrawn with the aid of syringes or so-called vacutainers in order to be able to carry out a large number of examinations with the body fluid sample. In a second area, however, liquids in the range of approximately 2 to 20 μl are removed in order to be able to carry out so-called rapid tests. This type of rapid test has become particularly popular in the area of blood sugar measurement. In addition, the rapid tests also cholesterol. Blood lipids. Drugs and other analytical parameters are determined. In terms of numbers, however, the blood glucose determination outweighs the rest of the evidence by a multiple. The reason for this is the relatively high proportion of diabetics in the population, the need for frequent measurements of blood sugar levels and the great medical benefit from knowledge of blood sugar levels. Regular monitoring allows the diabetic to recognize when their blood sugar level is outside the normal range and can take appropriate measures to bring the blood sugar level back into the normal range. Frequently exceeding the blood sugar level results in blindness and makes amputations of extremities necessary. The number of blindness and amputations has increased in recent years due to greater control of blood Sugar levels can already be significantly reduced with the help of cutting tests. For a short time, fatally high blood sugar levels are even more fatal than high blood sugar levels, which can lead to a so-called hypoglycemic shock in which the diabetic becomes unconscious and dies, unless he receives help from third parties.

Without going into more detail about the medical value of other rapid diagnostic tests, it follows directly from what has been said that there is a great need for a widespread use of rapid diagnostic tests and in particular rapid blood sugar tests. A number of test systems are already available on the market that manage with small amounts of capillary blood and provide reliable blood glucose results. A widespread use of such systems is not countered by the costs associated with testing, but by the removal of blood or body fluid that is still necessary for testing. In recent years, there have been many attempts to avoid taking blood entirely or to make blood collection as painless and pleasant as possible. A blood collection device that already enables largely pain-free and easy-to-use blood collection is described, for example, in US Patent RE 35,803. There are also a large number of other blood collection devices on the market which are also based on the principle that a sharp lancet creates a relatively small wound from which blood emerges. Furthermore, devices for removing interstitial fluid are known in the prior art, in which a thin cannula is inserted into the dermis and, by applying pressure to the area surrounding the puncture site, interstitial fluid is pressed out through the cannula. Common to both principles for the removal of body fluid is that a lancet or cannula remains which has been in contact with the body fluid and is therefore contaminated. Since these are extremely pointed objects, the risk of infection due to unintentional stinging is relatively high.

It was the object of the present invention. to provide a low-pain system for taking small amounts of body fluid that does not require a needle, cannula, or other pointed object to come into direct contact with the body fluid. The problem mentioned is solved by a system for the transdermal extraction of body fluids. which includes a device with which at least one particle is accelerated to a speed which allows the particle to penetrate the skin into the epidermis or dermis. The at least one particle should be free of the analyte to be determined in order to avoid interference with the analysis and the particle is still resorbed by the body.

Preferred embodiments of the system according to the invention relate to devices which support the leakage of body fluid and means for determining an analyte. that are integrated into the system.

The present invention is based on the observation that penetration of particles into an area of the skin can be associated with the escape of blood or interstitial fluid through the resulting skin opening. This observation is by no means new. which makes sense in terms of firearms. However, it is also directly apparent that direct use of firearms or the like is impossible for the purpose of the present invention, since the projectiles used are much too large, penetrate too deep into the body and cause too large, often life-threatening injuries. Furthermore, the projectiles used in the area of firearms are not absorbed by the body, which makes them unsuitable for the purpose according to the invention.

Devices for transdermal application of medicaments are known in the prior art, in which particles are shot into a skin surface. Such a projectile is known, for example, from US Pat. No. 4,326,524, but because of its size in the range of a few millimeters in diameter it is unsuitable for removing painful body fluids. A number of documents (for example US Pat. No. 5,630,796 and WO 99/04838) describe the subcutaneous application of small medicament particles by shot into the body. These documents give no indication that an injection of particles could also be suitable. To gain body fluids. Furthermore, the composition of the particles used is based on the therapeutic effect being pursued and in no way takes into account possible interference with an analytical determination. A system in the sense of the present invention is used to obtain small amounts of body fluids. The amounts of body fluid that are obtained are typically in the range of about 0.1-2 μl. Body fluids in the sense of the invention are to be understood in particular as blood and interstitial fluid (ISF). Blood can be obtained by injuring the capillary network in the boundary layer between the dermis and epidermis or in the dermis. The penetration depth for this, depending on the person, is approximately 500 μm. For ISF removal, it is advantageous to let the particles penetrate into the boundary layer between the epidermis and dermis or a little deeper. In the context of the present invention, penetration depth is understood to mean the distance between the skin surface and the center of gravity of the respective particle. The preferred collection point for capillary blood is the fingertips, since the skin openings made here do not close again immediately, so that sufficient blood can escape to the outside. On the other hand, the removal of blood from the so-called plate skin, as is present on the forearm, is less painful. However, additional measures will usually be required to keep a channel created in the skin surface open in order to allow enough blood to escape. No capillaries have to be injured to remove interstitial fluid. According to current knowledge, interstitial fluid is an ultrafiltrate of capillary blood, in which blood sugar can be detected using the same methods as in capillary blood.

A system according to the present invention includes a device for the transdermal application of particles. To do this, the particles must be accelerated to a speed sufficient to allow them to penetrate into the epidermis or dermis. Suitable accelerators can be based on different principles. For example, it is possible to detachably attach the particles to a carrier which is accelerated and which remains within the acceleration device while the particles detach and penetrate into the body. A device for this purpose, which is based on an electromagnetic principle, is described in WO 99/04838, to which reference is hereby made in full. Another way to accelerate the particles to the necessary speeds is to apply them to a membrane that is accelerated by a pressure surge. Suitable devices are described for example in US 5,204,253 and US 5,630,796. Regarding the methods for accelerating particles, the Full reference to the aforementioned documents. A device for the transdermal application of particles can in principle be designed in accordance with the device shown in US Pat. No. 5,630,796, in which a tube is provided. which is placed with its open end on a skin area and which creates a defined distance between a reservoir for the particles and the skin surface. According to the aforementioned documents, the particles according to the present invention can also be arranged in a reservoir which surrounds the particles without contamination and which opens when the acceleration device is actuated.

In the context of the present invention, it is preferred to accelerate and allow the particles to penetrate substantially perpendicular to the skin surface. In principle, however, it is also possible to apply the particles at an angle to the skin surface.

The particles that are administered transdermally should be essentially free of constituents that interfere with a subsequent analysis. In particular, the particles should be free of the analyte or analytes that are determined. On the other hand, admixtures of the analyte can be tolerated if their concentration is so low that a subsequent analysis is not significantly falsified. In this context, it is favorable that a dissolution of the particles, which could lead to contamination, is generally slower than an escape of body fluid. This means that proportions of the analyte in the particles can be tolerated under certain circumstances. Another criterion for the particles is that they should be essentially completely absorbed by the body. Gelatine has proven to be suitable. Sugar. Proteins. Ice and mixtures of the substances mentioned have been proven. For the detection of blood sugar (glucose), sugars such as e.g. Sucrose. Fructose and mannose can be used. It has proven to be advantageous in order to obtain an essentially painless extraction of body fluid. Use particles with a diameter of less than 700 μm. The particles can be in the form of spheres, for example. Have ellipsoids or discs.

As already mentioned at the beginning, the system according to the following invention is particularly suitable for the collection of capillary blood and interstitial fluid. It turned out. that different parameters regarding particle size and speed are advantageous for these two types of body fluids.

It is favorable for obtaining capillary blood. To use particles with a diameter in the range between 100 and 500μm, since there is a sufficient probability in this size range to hit a capillary with just one or a few particles. The depth of penetration of the particles into the skin for the collection of capillary blood should be between 0.5 and 1.3 mm. It has been shown that such a penetration depth can be achieved with a particle speed in the range from 500 to 1500 m / sec for particles between 100 and 500 μm diameter and a density of approximately 1 g / cm ³ .

For the extraction of interstitial fluid, on the other hand, it is advantageous to use a large number of smaller particles which penetrate to a depth of approximately 50 to 500 μm. It turned out to be cheap. To use particles with a diameter in the range of 20 to 100 μm, which are accelerated to a speed in the range of 500 - 1500 m / sec. To with

Particles of this size can convey a sufficient amount of interstitial fluid, it is preferred to use 100-10,000 particles simultaneously.

It is an advantage of the system according to the invention. that the skin openings formed by the particles are kept open by the particles themselves when the particles get stuck at a suitable depth. If only one skin opening were to be formed - in a soft way too - the opening in the area of the plate skin closes automatically, which hinders the extraction of body fluid.

A system according to the invention can be used in the form described above. to deliver body fluid to the body surface, from where it is applied to a test element or the like to perform an analytical test. This corresponds to the use of blood collection devices customary in the market today, in which a wound is produced by a lancet and leaked blood is applied by patients to a test strip. However, a system according to the invention can also be equipped with means that absorb the body fluid that is being conveyed, such as, for example, capillaries or capillary-active (absorbent) materials. These means for absorbing body fluid are preferably directly Nem test element connected to carry out an analytical test, so that the absorbed body fluid is supplied to the test element. The supply of interstitial fluid with a capillary to a test membrane is described, for example, in US Pat. No. 5,820,570. A corresponding arrangement for the supply of blood via a capillary to a test membrane is described in US Pat. No. 4,637,403.

Within the scope of the present invention, automated introduction of a test element to the exit point of the body fluid is also favorable. In this way, a capillary can be avoided which is an additional disposable part and which is also disadvantageous in terms of production technology. The test element advantageously has a region with which it can be brought up to the body fluid located on the body surface and which contains no reagent or a test chemical. This can prevent chemical substances from getting into the body opening. In particular, the glucose oxidase used in many tests can lead to irritation.

Furthermore, a system according to the invention can also include means for determining an analyte. Such an agent can be, for example, a test element that changes color when it is moistened with the analyte. Such a color change can then be evaluated visually or colorimetrically with a photometer in order to enable a quantitative determination of the analyte. Since such test elements and photometers are well known to the state of the art for their evaluation, this will not be discussed in more detail here. Furthermore, an analyte can be determined with the aid of a measuring cell, such as an electrochemical measuring cell. For a glucose determination, for example, measuring cells are used in which glucose oxidase is applied to an electrode and an uncoated metal electrode is used as the counter electrode. The measured change in potential is based on the formation of hydrogen peroxide on the electrode coated with glucose oxidase. Electrochemical test elements are also known in the prior art, as are described, for example, in EP-B-0505475, in which the so-called Kottrell current is measured. This description of devices for determining analytes is merely exemplary in nature. Of course, a multitude of further devices for analyte determination are known to the person skilled in the art which can be used in the context of the present invention. The means for determining an analyte can be integrated into a system according to the invention, for example, by coupling the means for determining the analyte to the means for absorbing body fluid, so that when the means for absorbing body fluid is brought up to the leaked body fluid, a the agent for analysis is supplied directly with analyte. Furthermore, the means for determining the analyte can also be integrated into the system according to the invention in such a way that it is either so close to the point of exit of body fluid that it is supplied directly with body fluid or the means for analysis can be brought up to the body fluid, for example, by a movable arrangement of the means for analyte determination in the system.

It is also advantageous in the context of the present invention. Provide means to support leakage of body fluid. In US Pat. No. 5,820,570, an arrangement is described in FIG. 2 in which the lower edge of a housing, which is located at a lateral distance from the point of withdrawal of body fluid, is pressed onto the body surface, and in this way body fluid from the tissue is pressed out. WO 97/42886 also describes a method for removing body fluids, in which the housing of a blood sampling device is repeatedly pressed against the body surface in such a way that a ring of tissue is pressed down, so as to squeeze body fluid out of the exit point. US Pat. No. 3,626,929 also describes a method and a device in which a wound is created on the tip of the finger and the proximal part of the finger is pressed periodically in order to promote blood leakage. In the context of the present invention, means for supporting an escape of body fluid are to comprise devices which exert pressure on a skin area which has penetrated the skin area into which the at least one particle has penetrated. is adjacent. Means are also to be included which include an ultrasound device, as described, for example, in WO 94-08655 and US Pat. No. 5,458,140. Finally, means are also to be included which, in order to support the exit, have a device for applying a negative pressure to the area of the skin, into which the at least one particle has penetrated.

The present invention is explained in more detail with the aid of some figures. Figure 1: Penetration of a particle in a skin area and leakage of blood

Figure 2: Electromagnetic system for accelerating particles

Figure 3: Detachable attachment of particles

Figure 4: Packaging for particles

Figure 5: Cross-sectional packaging shown in Figure 4

Figure 6: Electromagnetic system for accelerating one or less

particle

FIG. 1 shows in representations A to C the penetration of a particle and the escape of blood. FIG. 1A shows the movement of the particle (10) onto the body surface. The skin layers epidermis and dermis can also be seen from the figure. Blood-carrying capillary loops (20) are present in the dermis.

Representation B shows a state in which the particle has penetrated the epidermis and is in the dermis. When entering the dermis, the capillary loops shown were partially damaged so that blood can escape from them. FIG. 1C shows how blood exits the capillary loops from the skin through the opening caused by the particle and how a drop of blood (30) forms on the surface of the body.

FIGS. 2 to 6 show systems for accelerating particles which are taken from international application WO 99/04838.

Figure 2 shows an electromagnetic system for accelerating the particles (10). A thin metal band (101) is arranged in such a way that regions of the band which lie opposite one another result. If a current pulse is applied to the metal strip at its ends, the opposite parts of the metal strip collide due to the electromagnetic waves generated Fields. The lower part of the metal strip is in contact with a replacement bearing (102). so that he cannot dodge down. Accordingly, the upper part of the metal strip is thrown upwards by the electromagnetic repulsion, as shown in FIG. 2B. The particles (10) are located in a reservoir which is closed by a plastic skin (103). The plastic skin has a predetermined breaking point (104). which tears open when the upper part of the metal strip is thrown away. As a result, the particles (10) are released and fly towards a body surface at a speed which is essentially determined by the speed of the metal strip. to penetrate the skin there.

An alternative fastening of the particles is shown in FIG. This consists in that the particles are detachably connected to a surface (1 10). The surface (1 10) can be a double-sided adhesive tape, which in turn is attached to a plate (1 1 1). The plate (1 1 1) can be accelerated in the direction of the particles, and when the plate is braked, the particles detach from the surface (1 10) due to their inertia and fly towards the surface of the skin. The plate (1 1 1) can be accelerated mechanically, for example, by a spring arranged on the side opposite the particles, by a pressure surge, or else using the electromagnetic principle shown in FIG. 2. Another possibility is to use a plate which has a depression in the region shown in FIG. 3A and the remaining region of the plate is planar. When the plate is bent at two opposite ends in the direction of the depression, the depression suddenly bulges out due to mechanical tension. as shown in Figure 3, and accelerates the particles.

FIG. 4 shows a further possibility of a reservoir for particles, as can be used for example in connection with the device shown in FIG. 2. The particles are in a plastic container, which is folded at its ends and in which

Has a predetermined breaking point (104) in the middle. When the carrier plate (101) accelerates and then brakes, the reservoir (103) tears open along the predetermined breaking point (104) and releases the particles. This is shown further in FIG. 5.

FIG. 6 shows an exchangeable module with a reservoir for particles. The arrangement is based on the electromagnetic drive principle, as has already been described in connection with FIG. 2. The particles (10) are located in the recess (101 a) of an electrically conductive capable band (101), which is arranged M-shaped in the example shown. If a current pulse is applied to the contacts (105), the opposite arms of the electrically conductive tape repel one another and the outer regions are pressed against the walls (106) of the housing (108). By moving the arms apart, the U-shaped part of the band in which the particle (10) is located is stretched and the particle (10) is thrown upwards out of the housing. The module shown in FIG. 6 also has a sealing film (109) with which the space in which the particles are located is sealed off from the outside space. This can ensure sterility of the particles entering the body. Before the module shown is used to introduce the particles into the body, the sealing film (109) is removed.

Claims

claims

1. System for the transdermal extraction of body fluid for the determination of at least one analyte. including

a device for the transdermal application of at least one particle, with an acceleration device which accelerates the at least one particle to a speed which enables the particle to penetrate into an area of the skin as far as the epidermis or dermis, and a release mechanism for triggering the acceleration device,

a reservoir for the at least one particle.

2. System according to claim 1, wherein the at least one particle is substantially free of the at least one analyte to be determined.

3. System according to claim 1, wherein the at least one particle is such that it is substantially completely absorbed.

4. System according to claim 1, wherein the at least one particle consists essentially of gelatin.

5. The system of claim 1, wherein the body fluid is blood, the diameter of the at least one particle is between 100 and 500 microns and the accelerator accelerates the at least one particle to a speed in the range of 500 to 1500 m / s.

6. System according to claim 5, wherein between 1 and 10 particles are accelerated simultaneously.

7. System according to claim 1, wherein the body fluid is interstitial fluid and a plurality of particles with a diameter in the range of 20 to 100 microns are accelerated simultaneously to a speed in the range of 500 to 1500 ms.

8. The system of claim 7, wherein the plurality comprises 100 to 10,000 particles.

9. The system of claim 1 including means for absorbing body fluid.

10. The system of claim 9, wherein the means for receiving body fluid is a capillary or a capillary active material.

11. System according to claim 1 or 9, which includes means for determining an analyte.

12. System according to claim 1, 9 or 11, which has means for supporting an escape of body fluid from the skin area.

13. The system of claim 12, wherein the exit support means is a

Ultrasound device is.

14. The system of claim 12, wherein the exit support means is a

Device for applying a vacuum to the skin area is.

15. The system of claim 12, wherein the means for assisting the exit means for exerting a pressure on a second area of the skin, the area of the skin into which the at least one particle has penetrated. is adjacent.