CA2205444A1

CA2205444A1 - Transdermal system

Info

Publication number: CA2205444A1
Application number: CA002205444A
Authority: CA
Inventors: Carlo Stefan Effenhauser; Andreas Manz
Original assignee: Individual
Current assignee: Novartis AG
Priority date: 1994-12-09
Filing date: 1995-11-27
Publication date: 1996-06-13
Also published as: WO1996017648A1; DE59505328D1; AU4256496A; JPH10510175A; EP0796128B1; ATE177325T1; EP0796128A1

Abstract

A transdermal system (1) for delivering a substance through the skin (2) has a reservoir (11) which stores the substance for delivery and a transfer device which in operation is connected to both the reservoir and the skin by means of passage openings. This transfer device comprises a sheet substrate (12) with up to about 30 % porosity. When the substance is delivered using an electrical field, the substrate sheet is a poor electrical conductor or essentially a nonconductor.

Description

FO/67-20247/A CA 0220~444 1997-0~
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Transdemmal system The invention relates to a transdermal system according to the preamble of the independent patent claim.

In the administration of substances, it is possible to differentiate in principle between invasive systems and non-invasive systems. Invasive systems are distinguished essentially by the fact that with those systems the skin, especially the outermost layer of skin - the so-called stratum corneum - is clearly penetrated through and layers of skin Iying below it are at least penetrated into if not also penetrated through (for example in the case of intravenous or intramuscular injections). That type of administration is customarily effected using a normal injection needle.

Non-invasive systems are distinguished precisely by the fact that they do not comprise such through-penetration. A typical example of such non-invasive systems is the transdermal patch. Transdermal systems, especially transdermal patches, are nowadays customary forms of administration for many types of substances, especially also for pharmaceutically active ingredients or active ingredient mixtures.
Such systems function essentially by administering a specific amount of a desired substance from a reservoir to a patient through the skin.

A very typical example of non-invasive transdermal systems is the conventional transdermal patch. The substance is administered either by diffusing spontaneously from the reservoir through the skin (operative force: concentration gradient) or by being transported from the reservoir through the skin, for example, by iontophoresis, that is to say by means of an electric field generally produced by means of electrodes (voltage gradient). In principle, the substance may also be transported by other operative forces, for example by pressure gradients that are constant or variable over time.

In practice, transdermal patches in which the substance to be administered diffuses spontaneously from the reservoir through the skin allow only the administration of small amounts of a substance per unit of time, simply because the diffusion process CA 0220~444 1997-0 through the natural channels of the skin (sebaceous glands and sweat glands, inter-and trans-cellular transport pathways, hair follicles) proceeds slowly. The mainreason for that, especially in the case of the pharmaceutically active proteins and peptides that can be prepared by means of gene technologyl but also in the case of other pharmaceutically important classes of substances, for example oligo-nucleotides and carbohydrates, is that those substances have large, polar and usually electrically charged hydrophilic molecules. The hydrophilic nature, however, restricts the transport through the very lipophilic stratum corneum quite considerably.

On the other hand, such proteins and peptides cannot, in practice, be administered orally. That is because they are either decomposed or so altered in the gastro-intestinal tract that the desired pharmaceutical action no longer occurs, or arecorrespondingly decomposed or so altered by the liver that the desired pharma-ceutical action does not occur ("first pass" effect). In principle, therefore, parenteral (e.g. intravenous, subcutaneous or intramuscular) administration comes into consideration. Especially in long-term treatment with the requirement of regularinjection of a substance - often several times per day - considerable demands are made on the patient, which, inter alia, prejudices the co-operation of the patient in adhering to the dosage scheme (compliance). An alternative to parenteral administration is therefore necessary.

Administration by means of transdermal systems, especially by means of the conventional transdermal patches, however, allows only the administration of usually electrically uncharged substances having a molecular size that does not exceed certain limits. Larger and/or electrically charged molecules cannot penetrate through the natural skin channels or cannot penetrate through them sufficiently rapidly.

For that reason, EP-A-0 429 842 and also WO-A-93/17754 each propose a transdemmal patch that has a transfer device in the form of a membrane that is provided with needles. Inside each of the needles there is a channel which is connected at its proximal end to a reservoir in which the substance to be administered is stored and which has at its distal end an opening through which the substance can emerge. On application of the patch to the skin, the needles pierce CA 0220~444 1997-0 through the skin and the substance can be administered to the patient from the reservoir through the artificial channels in the needles.

In that manner, it is, in principle, possible for the substance to be administered to the patient not through the natural skin channels but through the channels in the needles. In principle, that also enables the administration of substances comprising molecules of such a size that they could not be administered through the naturalskin channels (sebaceous glands, sweat glands, hair follicles). Moreover, in principle also hydrophilic substances, such as the peptides or proteins already discussed, which otherwise would not be able to pass through the lipophilic stratum comeum at all or only with difficulty, can be administered readily in that manner.

A disadvantage of the transdermal patches described in the two patent applications mentioned is, however, that the external dimensions of the needles are comparatively large. In the patch according to EP-A-0 429 842 each individual needle has a diameter in the range from 50 !lm to 400 ~lm. In the patch according to WO-A-93/17754, even external diameters of 1 mm are indicated for the needles, the internal diameter (that is the diameter of the channel) being 500 ~lm.

Moreover, the needles described in those two patent applications are also up to 2 mm in length (EP-A-0 429 842) and have a distribution density of from 1 to 15 needles per square centimetre, or have a length of 30011m (WO-A-93/17754).

With both patches, it is of course possible and even to be expected that there will be not inconsiderable irritation of the skin on account of the large external dimensions of the individual needles and also on account of their length (the needles may penetrate more deeply than just through the stratum comeum which consists of dead cells and which, in humans, is from 10 to 20 llm thick). Moreover, the manufacture of such a patch having a large number of individual needles is very complicated and not suitable for mass production. If the substance is administered by iontophoresis, that is to say by means of a current which necessarily also flows through the skin, then, because of the relatively small number of channels, a comparatively strong current must flow through each individual channel in order to render possible the transport of a specific amount of a substance, that is to say the CA 0220~444 1997-0 current density (current/area) in the individual channels will be comparatively high.
Such comparatively high current densities may likewise result in irritation of the skin.

The problem underlying the present invention is therefore to propose a transdemmal system that does not have the afore-mentioned disadvantages, that thus enables the administration of a specific amount of a substance - irrespective of whetheradministration is effected by means of iontophoresis or not - and that avoids irritation of the skin as fully as possible. Moreover, it should be possible for the transdermal system to be manufactured cost-effectively in large numbers (mass production) .

According to the invention there is therefore proposed a transdermal system in which a transfer device, which is connected both to a reservoir containing the substance to be administered and to the skin, comprises a substrate sheet, the porosity of which is up to approximately 30 %. The mentioned porosity of the sheet on the one hand enables a specific amount of a substance actually to pass through the channels and thus to be administered, and on the other hand enables the dimensions of the channels to be kept so small that irritation of the skin resulting from the penetration of the outermost layer of skin either does not occur at all or occurs only to an extremely small degree. Such substrate sheets having a very large number of individual channels per unit surface area (in the case of needles, for example, two thousand five hundred channels per square centimetre) can be manufactured, preferably monolithically, in simple manner by known micro-mechanical manufacturing processes, for example photolithography, X-ray Iithography or electron beam lithography, with the result that even the manufacture of such extremely small structures is not associated with any kind of technical difficulty or particular expense. Moreover, such manufacturing processes also enable the manufacture of extremely sharp-edged structures so that only very little pressure is required in order to penetrate through the outermost layer of skin, which means that the patient will not experience any pain when the transdermal system is applied.

Especially in the case when the administration is effected using an electric field (for example iontophoretically), the substrate sheet is in the form of a poorly conductive or substantially non-conductive substrate sheet (it may in principle alternatively be a conductive substrate surrounded by an insulating layer or a layer for improving skin CA 0220~444 1997-0~
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compatibility). Provided that is not the case, the substrate sheet may also consist of a conductive material.

Further advantageous forms of the transdermal system according to the invention,especially those which relate to the geometry and the distribution of the openings over the substrate sheet (needles, ribs, etc.) and also to the arrangement, dimensions and measurements thereof, will be found in the dependent claims.

Conditional upon the relatively high porosity (ratio of open area available for the transport of substance into and through the epidermis to the total surface area of the substrate sheet), the electrical resistance and the resistance to permeation is substantially reduced in comparison with intact stratum corneum. Whilst the electrical resistance of an area of skin of one square centimetre is in the range from a few 1 o3Q to a few 1 04Q, the corresponding resistance for a substrate sheet of the same size having a porosity of 3 % may be approximately from 50 to 100 Q. The amount of transported molecules of substance is proportional to the amount of charge transported during administration, that is to say for a predetermined period of administration it is proportional to the strength of the current. On account of the lower electrical resistance, that strength of current can be produced, however, with a substantially lower voltage; moreover at the same strength of current the electrical heat loss is substantially reduced. Thus, either a higher current can flow with the same heat loss, which corresponds to a greater amount of substance transported, or there is correspondingly less heat loss with the same current, with the result that there is no irritation of the skin or, at least, significantly less irritation. Moreover, it is also very clear that the high porosity also allows the manufacture of transdermal systems (e.g. patches) having a comparatively small surface area that nonetheless enable a sufficient amount of a substance to be administered.

The invention is described hereinafter in greater detail with reference to drawings, some of which are highly schematic:

Fig. 1 is a detail of an embodiment of the transdermal system according to the invention showing the essential parts;

Fig. 2 is a perspective view of a detail of the substrate sheet of Fig. 1;

CA 0220~444 1997-0 Fig. 3 is a plan view of a further embodiment of a substrate sheet of the transdemmal system according to the invention, the density of distribution of the openings varying over the surface of the substrate sheet;

Fig. 4 is a plan view of a further embodiment of a substrate sheet of the transdermal system according to the invention, the density of distribution of the openings likewise varying over the surface of the substrate sheet;

Fig. 5 is a plan view of a further embodiment of a substrate sheet of the transdermal system according to the invention;

Fig. 6 and Fig. 7 are each a detail of an embodiment of a substrate sheet with the channels and ribs shown on a greatly enlarged scale;

Fig. 8 is a plan view of a further embodiment of a substrate sheet with the openings in a zigzag arrangement;

Fig. 9 is a plan view of a further embodiment of a substrate sheet having periodically recurring structures in the form of crosses;

Fig. 10 is a view of a detail of a further embodiment of a substrate sheet having openings that extend in curved lines;

Fig. 11 is a view of a detail of a further embodiment of a substrate sheet having blades that are arranged offset in height; and Fig. 12 is a view of a further embodiment of a substrate sheet that is in two parts.

For the purpose of clarity, the detail of an embodiment of the transdermal system according to the invention shown in Fig. l shows only very essential parts of the system on a greatly enlarged scale. The transdermal system 1 comprises a first electrode 10 (the corresponding counter-electrode has not been shown since the Fig. shows only a detail), a reservoir 11 in which the pharmaceutically active substance to be administered is stored, and also a substrate sheet 12, acting astransfer device, which is connected to the reservoir 11 by means of proximal openings 120 and which comprises channels 121 that open into distal openings CA 0220~7444 1997-0~7-l~7 122, with the result that the reservoir 11 is connected to the skin 2 of a patient once the transdermal system has been applied.

The skin 2 of the patient is here represented in a highly simplified manner, namely by an outer layer of dead skin cells, the stratum corneùm 20, and by an epidemmal layer 21 Iying beneath it from which cells continuously grow into the stratum comeum 20, since the cells of the latter are shed over time and must be replaced.
For the purpose of clarity, further details of the skin have not been shown.

The substrate sheet 12 has on its side facing the skin (the underside in Fig. 1 ) numerous individual very fine needles 123. For the purpose of clarity in Fig. 1 and also in Fig. 2, those very fine needles are represented in a highly exaggerated manner. In reality, the needles 123 are extremely fine and pointed individual needles. Extending in each of those fine needles 123 is a separate channel 121 which connects each proximal opening 120 to a respective distal opening 122. In order to produce the so-called operating state, such a transdermal system is attached to the skin 2. The length of the individual needles 123 is so dimensioned that when the system (e.g. a patch) is pressed onto the skin 2 the individual needles 123 pierce the stratum comeum 20 completely or partially whilst the epidermal layer 21 Iying beneath it remains largely or even completely unaffected. The result is that in that manner artificial channels into and through the lipophilic stratum corneum 20 are created through which the substance, even if it is a hydrophilic substance or a substance having very large and/or electrically charged molecules, especially a7so proteins or peptides, can be administered to the patient from the reservoir 11. In view of the short length of the needles 123, which will be discussed hereinbelow, the patient will experience no pain when the system is applied. The administration can therefore be described as a substantially non-invasive method of administration.

The substance can then be administered from the reservoir 11 through the proximal opening 120 in the substrate sheet 12 through the channel 121 and through the distal opening 122 of the respective needle 123 to the patient. This may either occur passively, that is by diffusion of the substance from the reservoir 11 into the skin of the patient or, alternatively, it can also be promoted, for example by means of electrophoresis, that is by means of an electric field or by means of an electric current. That current flows from the first electrode 10 through the skin to the CA 0220~444 l997-0 corresponding counter-electrode (not shown in Fig. 1). The latter may be so arranged, for example, that it surrounds the transdermal system in an annular manner, as it were, in a manner similar to that described for the corresponding counter-electrode in WO-A-93/17754.

The substance itself may or may not be electrically charged (ionic). In the case of electrically charged substances, it is very clear that they are transported into and through the skin by the force acting upon them by virtue of the electric field between the electrodes. In the case of eiectrically neutral substances, transport is effected by means of electro-osmosis.

In a transdermal system as described above, the porosity, that is the ratio of the area of all the distal openings 122 to the total surface area of the substrate sheet 12, is up to approximately 30 %. Such porosity enables the transport of a relatively large amount of the substance, even in the case of passive administration, because the effective area through which the substance is supplied to the skin is significantly larger than in the case of conventional transdermal systems. As regards implementation by means of individual needles, the number of distal openings 122provided on the substrate sheet may be, for example, approximately two thousand five hundred per square centimetre. The length LN of the individual needles 123 may be up to approximately 1000 ~,lm, preferably approximately from 1 to 500 ~,lm, the total length LK of the channels 121 in the individual needles 123 may be up to approximately 3000 llm, preferably approximately from 10 to 1000 llm, and the diameter of the channels may be from approximately 0.03 llm to approximately 300 ~um, preferably approximately from 0.1 to 100 llm. The substrate sheet may be made, for example, of an insulator or a semi-conductor, preferably silicon, ceramics, glass or a polymer (in the case of administration without an electric field also an electrically conductive material). The effective combined electrical resistance is thus substantially determined by the substance or, since typically the substance is dissolved, by the corresponding solution. A typical value for the combined electrical resistance is in the range from approximately 50 to 100 n. That value is significantly less than the value of the electrical resistance demonstrated by the natural channels of the str~tum comeum which is typically in the range from a few 103 Q to a few 104 Q. In view of the lower resistance, the same strength of current can be achieved with a substantially lower voltage and, with the same strength of current, the heat CA 0220~444 1997-0~

loss is substantially less. In that manner, irritation of the skin, which may occur with higher resistances (as a result of greater warming of the tissue), is avoided entirely or is at least reduced to a very low level. With the same heat loss, a higher current strength is possible, as a result of which more substance can be transported. Onaccount of the lower resistances, higher currents may i`ndeed be used without such irritation of the skin occurring, with the result that it is possible to administer significantly greater amounts of a substance than is the case with conventional transdermal patches. Moreover, the resistance in the "artificial" channels does not change over time as is quite customary, by contrast, in the case of administration through the natural skin channels of the stratum comeum, so that when using the transdermal system according to the invention it is also possible for the amount of the substance to be administered to be controlled substantially more precisely. Also, contact impedances which may occur between the patch and the skin are avoided by the transdermal patch according to the invention. Furthermore, by shortening the natural permeation pathways, the response time, that is to say the interval between applying the patch and obtaining a steady state of penetrating molecules, is substantially shortened.

Further embodiments or developments of the substrate sheet 12 will be found in Figs. 3 and 4, the plan view in each case being shown from the reservoir side. In both those embodiments, the density of distribution of the proximal openings 120(and thus also the distribution of the channels 121 and of the needles 123, and also of the distal openings 122 on the side of the substrate sheet 12 facing the skin) is not homogeneous over the entire surface area, that is to say it varies. Two suchvariants are shown in Figs. 3 and 4. In view of the fact that, in practice, currents flow only through the individual channels, it is possible - by varying the density ofdistribution of the proximal openings 120 over the surface area of the substratesheet 12 - to simulate, as it were, a corresponding electrode shape. In the case of the embodiment in Fig. 3, that is a ;'rectangle within a rectangle"; in Fig. 4 the simulated electrode is circular.

It is, however, by no means necessary for the porosity of the substrate sheet to be produced by individual discrete openings (needles). Completely different structures are also possible, as illustrated especially by Fig. 5. There it can be seen that the openings (again the proximal openings 1 20a of a substrate sheet 1 2a are shown)are essentially in the form of straight lines. The distal openings on the side of the CA 0220~444 1997-0~

substrate sheet 12a facing the skin are then in the form of ribs extending substantially in straight lines, each having extremely fine blades which penetrate into the stratum comevm. Each distal opening extends substantially along the entire length of the respective rib.

Figs. 6 and 7 show a detail of a substrate sheet, in which such ribs 123a can beseen on a greatly enlarged scale. It can be seen that each of the individual ribs 123a comprises two sharp-edged blades 124a and 125a. In one case (Fig. 6), the dimensions of the channel 121 a are constant along its length and in the other case (Fig. 7) the channel narrows conically towards the blades.

The individual proximal openings (and, accordingly, the ribs and their blades on the distal side of the substrate sheet) may alternatively be in the form of zigzag lines 120b, as shown in Fig. 8, or in the form of other periodically recurring patterns, for example in the form of crosses 120c, as shown in Fig. 9. Moreover, the individual proximal openings 120d may also extend in curved lines, as shown by way of a detail in Fig.10, the blades 124d and 125d on the distal side of the substrate sheet extending accordingly.

Furthermore, Fig.11 shows a further variant in which the blades 124e and 125e are, as it were, offset in height. As a result, the first blade 125e to come into contact with the skin "cuts open", as it were, the stratum comeum and the second blade 124e then follows into the incision, thereby avoiding the possibility of tissue coming between the very sharp blades and thus blocking the distal opening 122e. That risk is admittedly low even in the case of blades that are not offset in height, but is reduced still further by that measure.

Finally, Fig.12 shows another variant in which the substrate sheet comprises twoparts 12f and 129. That variant of a substrate sheet is advantageous insofar as, for example, the part 129 may be in the form of a very thin lamina which, in the region of the needles or ribs and blades, has sufficient rigidity to penetrate into the stratum comeum but, on the other hand, has a certain flexibility so as to be able, on application of the transdermal system, to yield to a certain degree to small deformations of the skin. Such laminae may be made specially from a material that is very compatible with skin.

CA 0220~444 1997-0~
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All the described transdermal systems and the extremely fine structures of the substrate sheet can be manufactured, for example, by means of known micromechanical processes, such as photolithography, electron beam lithography or X-ray lithography, by means of galvanic moulding and by means of plastics casting processes, by means of etching and ablative processes or by means of laser machining. Also, not only may the transdermal systems described above be used for administering a substance from a reservoir, but also certain substances occurring in the skin may be transported out of the skin by means of the transdermal system according to the invention (reverse process), which can be very useful especially for analytical or diagnostic purposes, since in that manner it is possible to draw conclusions as to the presence of a specific substance in the skin or of a specific amount of a specific substance in the skin, and that in turn enables further conclusions to be drawn.

Claims

What is claimed is:

1. A transdermal system (1) for transporting a substance through the skin (2), comprising a reservoir (11) in which the substance to be transported is stored and a transfer device which, in the operating state, is connected both to the reservoir (11) and to the skin by means of openings, wherein the transfer device comprises a substrate sheet (12, 12a, 12b), the porosity of which is up to approximately 30 %.

2. A transdermal system according to claim 1, wherein the substrate sheet (12, 12a, 12b) is poorly conductive or substantially non-conductive.

3. A transdermal system according to either claim 1 or claim 2, wherein there isformed on the surface of the substrate sheet (12a, 12b) facing the skin (2) at least one rib having blades, in which rib there extends a channel, the openings (120a,120b) of which are connected at the proximal end to the reservoir and at the distal end to the skin, and which rib has at the distal end an opening, the distal opening extending substantially along the entire length of the rib.

4. A transdermal system according to claim 3, wherein the rib is substantially in the form of a straight line.

5. A transdermal system according to claim 3, wherein the rib and its blades are in the form of zigzags.

6. A transdermal system according to claim 3, wherein the rib and its blades are in the form of curved lines.

7. A transdermal system according to claim 3, wherein numerous periodically recurring structures are provided on the surface of the substrate sheet facing the skin, each individual structure comprising ribs having blades.

8. A transdermal system according to any one of claims 3 to 7, wherein the blades of the ribs are arranged offset in height.

9. A transdermal system according to claim 1, wherein numerous needles (123) areprovided on the surface of the substrate sheet facing the skin, in each of which needles there extends a channel (121), the openings (120,122) of which channel are connected at the proximal end to the reservoir and at the distal end to the skin.

10. A transdermal system according to claim 9, wherein the needles (123) are of conically narrowing construction at their distal end.

11. A transdermal system according to either claim 9 or claim 10, wherein the length (LN) of the individual needles (123) is up to approximately 1000 µm, especially approximately from 1 µm to 500 µm, and the total length (LK) of the channel extending through each needle is approximately from 1 µm to approximately 3000 µm, especially from approximately 10 µm to 1000 µm, and the diameter of the channel is from approximately 0.03 µm to approximately 300 µm, especially approximately from 0.1 µm to 100 µm.

12. A transdermal system according to any one of claims 1 to 11, comprising electrodes (10) which are so arranged that they produce an electric current running from the reservoir through the openings and the channels, which electric currenttransports the substance from the reservoir through the openings (120,122) and through the channels (121) into the skin (2).

13. A transdermal system according to any one of claims 3 to 12, wherein the density of distribution of the needles (123) or of the ribs on the surface of the substrate sheet (12) facing the skin varies.

14. A transdermal system according to any one of claims 1 to 13, wherein the substrate sheet (12,12a,12b) is manufactured, preferably monolithically, by a micromechanical manufacturing process, for example photolithography, X-ray lithography or electron beam lithography.