DE102012023343B4 - Layer structure for dispensing at least one active substance - Google Patents

Abstract

A layer structure for dispensing at least one active substance, the layer structure comprising: a carrier substrate, a plurality of active substance regions spaced apart from one another on the carrier substrate and containing at least one active ingredient, each of the active ingredient regions (101) is surrounded by non-active intermediate regions (102) of the carrier substrate, - a semipermeable cover layer (103) which is applied to the carrier substrate (100) and the drug regions (101) thereon and both the drug regions (101) and the non-active substance occupied intermediate regions (102) of the carrier substrate, wherein the semipermeable cover layer (103) in the non-active intermediate regions (102) directly or indirectly on the carrier substrate (100) adheres, each of the active substance regions (101) around the side and from above is enclosed by the semipermeable cover layer (103), so d in that active substance depots are formed, and - wherein the at least one active substance can diffuse outwards through the semipermeable covering layer (103).

Description

The invention relates to a layer structure for dispensing at least one active ingredient, a synthetic bladder and a catheter having such a layer structure and to a method for structuring a layer structure.

For many medical and non-medical applications, it would be desirable to have a layered structure that delivers at least one active ingredient evenly over long periods of time to a surrounding medium. It would be particularly desirable if the active ingredient could be reliably delivered over periods of months and years.

In the International Patent Application WO 2012/036618 A1 a polymer product is described which is designed to prevent the growth of fungi and other microbial substances. The polymer product comprises at least two layers, a functional layer comprising a polymer material and at least one antimicrobial substance, and a protective layer comprising a polymeric material attached to the functional layer externally and completely covering the functional layer, the protective layer having no antimicrobial substance ,

In the German Offenlegungsschrift DE 10 2009 007 667 A1 there is described a medical device that comes in contact with a human or animal body in use. The medical work equipment comprises a base body and a poly-parylene surface coating of the base body, wherein the surface coating comprises silver particles. In the preparation of the medical work equipment, a starting material containing parylene dimer is first evaporated to parylene monomers. The latter are then pyrolyzed to produce poly-parylenes. The poly-parylene is then deposited on the body in a nanoscale silver particle-containing atmosphere.

It is an object of the invention to provide a layer structure for dispensing at least one active ingredient, which delivers the active substance or active ingredients continuously and reliably over long periods of time.

The object of the invention is achieved by a layer structure for dispensing at least one active substance according to claim 1, by an artificial bladder according to claim 10, by a catheter according to claim 11 and claim 13 and by a method for structuring a layer structure according to claim 15.

A layered structure according to embodiments of the present invention is configured to deliver at least one active ingredient. The layer structure comprises a carrier substrate and a plurality of active substance regions which are applied to one another on the carrier substrate and contain the at least one active ingredient, wherein each of the active ingredient regions is surrounded by non-active intermediate regions of the carrier substrate. In addition, the layer structure comprises a semipermeable cover layer which is applied to the carrier substrate and the active substance areas located thereon and covers both the active substance areas and the non-active intermediate areas of the carrier substrate, the semi-permeable covering layer adhering directly or indirectly to the carrier substrate in the intermediate areas not having active substance , Each of the active substance areas is surrounded on all sides and from above by the semipermeable cover layer so that active agent depots are formed, wherein the at least one active substance can diffuse outwards through the semipermeable cover layer.

The layer structure enables a continuous and reliable delivery of the at least one active substance over long periods of time, that is to say over a period of months and years, for example. Before delivery to the surrounding medium, the at least one active ingredient must diffuse through the semipermeable cover layer. In this case, the release rate with which the at least one active substance is released to the outside, depends on the thickness and nature of the semipermeable cover layer. By virtue of the properties of the semipermeable cover layer, it is therefore possible to precisely set the delivery rate for the at least one active substance.

Another advantage of the layer structure is that the active substance areas are completely enclosed by the semipermeable cover layer. The semipermeable covering layer prevents active substance particles which detach from the active substance areas from being released to the surrounding medium. With advanced consumption of the active ingredient material is prevented by the semi-permeable cover layer that the remaining active material is discharged uncontrollably to the outside.

The semipermeable cover layer can consist of a biocompatible material, for example of polyparylene. This is particularly important for applications of the layer structure in the medical field. The layer structure can thus be used in particular for the long-term uniform release of active ingredient in the field of medicine, but can also be moreover used for drug delivery in non-medical applications.

According to an advantageous embodiment of the invention, the layer structure is adapted to deliver the at least one active substance with a predetermined release rate to the outside.

According to an advantageous embodiment, the layer structure is designed so that the at least one active substance diffuses through the semipermeable cover layer and is released to the outside.

According to an advantageous embodiment, the active substance areas are applied in the form of a repeating pattern on the carrier substrate.

According to an advantageous embodiment, the different active substance regions are separated from one another by the intermediate regions which are not active-substance-occupied.

According to an advantageous embodiment, each of the active substance areas is completely covered by the semipermeable cover layer.

According to an advantageous embodiment, the semipermeable cover layer covers both the active substance regions and the intermediate regions of the carrier substrate which are not active-substance-occupied.

According to an advantageous embodiment, the at least one active ingredient comprises at least one of the following: a microbiologically active substance, an antibacterial active substance, an antibiotic, an immunosuppressant, a fungicide, silver, rapamycin, molybdenum trioxide.

According to an advantageous embodiment, the semipermeable cover layer is a polyparylene layer.

According to an advantageous embodiment, the carrier substrate is a carrier substrate, on which both the at least one active substance and the semipermeable cover layer are adhered.

According to an advantageous embodiment, the carrier substrate is polyurethane.

According to an advantageous embodiment, the carrier substrate is silicone.

According to an advantageous embodiment, the semipermeable cover layer is a polyparylene layer which has a thickness in the range of approximately 100 nm to 300 nm. According to an advantageous embodiment, the semipermeable cover layer is a polyparylene layer having a thickness in the range of about 30 nm to 10 μm.

According to an advantageous embodiment, the active substance areas have a thickness in the range of about 30 nm to 10 μm. According to an advantageous embodiment, the active substance areas have a thickness in the range of a few micrometers, preferably of about 2 micrometers.

According to an advantageous embodiment, each of the active ingredient areas does not exceed a predetermined maximum dimension.

According to an advantageous embodiment, the active substance areas each have a diameter of about 10 nm to a few millimeters. According to an advantageous embodiment, the active substance areas each have a diameter of a maximum of about 3 mm.

According to an advantageous embodiment, the semipermeable cover layer is designed so that the at least one active substance can diffuse through at a given diffusion rate.

According to an advantageous embodiment, the layer thickness of the semipermeable cover layer is selected so that a desired release rate for the at least one active ingredient is achieved.

According to an advantageous embodiment, the layer thickness of the semipermeable cover layer is selected such that a desired permeability of the semipermeable cover layer is achieved.

According to an advantageous embodiment, the layer thickness of the semipermeable cover layer is selected such that a desired diffusion rate of the at least one active substance through the semipermeable cover layer is achieved.

According to an advantageous embodiment, the width of the non-active intermediate regions between adjacent drug regions is chosen so large that a reliable adhesion of the semipermeable cover layer is ensured around an active ingredient area.

According to an advantageous embodiment, the semipermeable cover layer adheres to the non-active substance occupied intermediate regions on the carrier substrate even if in the active substance areas of the at least one active ingredient is completely or partially consumed.

According to an advantageous embodiment, the expansion and arrangement of the active substance areas are selected such that, when the layer structure is loaded laterally, the mechanical properties are essentially determined by the carrier substrate and the semipermeable covering layer.

According to an advantageous embodiment, the active substance regions and the non-active ingredient-containing intermediate regions are dimensioned such that the at least one active ingredient is also present in the middle of the non-active ingredient intermediate regions with a sufficiently high concentration.

According to an advantageous embodiment, the active substance areas are dimensioned such that active ingredient particles which are possibly dissolved out of the active substance areas when the semi-permeable cover layer is damaged are sufficiently small and harmless.

According to an advantageous embodiment, the carrier substrate to form the active substance areas on a plurality of recesses, in which the at least one active ingredient is introduced.

According to the embodiments of the present invention, a layer structure as described above is used for coating a surface of at least one of: a door latch, a support bar, a handle, a cable, a blister, a catheter, a ureter splint.

An artificial bladder according to embodiments of the present invention has on its inside an above-described layer structure for drug delivery.

A catheter according to embodiments of the present invention has on its inside or on its outside or both on the inside and on the outside of a layer structure for drug delivery described above.

According to an advantageous embodiment, the inside of the catheter has a layer structure for drug delivery as described above, wherein the active substance areas are formed in the form of longitudinally extending drug pathways on the inside of the catheter.

A catheter according to embodiments of the present invention has on its inside a layered structure for dispensing at least one active ingredient. The layer structure comprises a plurality of active substance areas which are applied to the inside of the catheter and which contain at least one active substance, wherein the active substance areas are separated from one another by intermediate areas which are not active substance-occupied. In addition, the layer structure comprises a semipermeable cover layer, which is applied to the inside of the catheter and the active substance areas located thereon, wherein the semipermeable cover layer adheres directly or indirectly to the inside of the catheter in the non-active intermediate areas. The semipermeable cover layer covers both the active substance areas and the non-active substance occupied intermediate areas, so that drug depots form, wherein the at least one active ingredient contained in the active substance areas can diffuse through the semipermeable cover layer to the outside.

According to an advantageous embodiment, the drug areas are applied in the form of extending in the longitudinal direction drug paths on the inside of the catheter, wherein the drug pathways are separated by not active substance occupied intermediate areas.

According to an advantageous embodiment, the at least one active ingredient is applied to the inside of the catheter by means of a doctor blade in such a way that active substance tracts extending in the longitudinal direction along the inside of the catheter are formed.

According to an advantageous embodiment, the catheter has a round or oval inner cross-section, wherein the at least one active substance is applied to the inside of the catheter by means of a doctor blade such that active substance tracts extending in the longitudinal direction along the inside of the catheter form.

According to an advantageous embodiment, the catheter has a star-shaped inner cross-section, wherein the at least one active substance is introduced into the tips of the star-shaped inner cross-section such that active substance paths extending in the longitudinal direction along the inner side of the catheter form.

According to an advantageous embodiment, the catheter has a star-shaped inner cross-section, wherein the at least one active ingredient by means of a doctor blade in the tips of the star-shaped inner cross-section is that formed in the longitudinal direction along the inside of the catheter extending drug pathways.

A method for patterning a layer structure in accordance with embodiments of the present invention comprises applying a plurality of active substance regions to a carrier substrate, wherein the active substance regions contain at least one active substance, and wherein each of the active ingredient regions is surrounded by non-active intermediate regions of the carrier substrate. In addition, the method comprises applying a semipermeable cover layer to the carrier substrate and the active substance areas located thereon, the semipermeable cover layer adhering directly or indirectly to the carrier substrate in the intermediate areas not having active substance. Each of the active substance areas is enclosed on all sides laterally and from above by the semipermeable cover layer, so that active agent depots form, which are covered to the outside by the semipermeable cover layer.

According to an advantageous embodiment, the application of the plurality of active substance areas to the carrier substrate comprises an application of at least one of the following methods: electroplating; sputtering; sputtering; evaporation; Diving; Spray; spin; chemical vapor deposition; physical vapor deposition; squeegees; printing; Depositing material from a reaction solution on the carrier substrate; Depositing material from a Tollens reagent on the carrier substrate by a Tollens method; Depositing silver from a Tollens reagent on the carrier substrate by a Tollens method.

According to an advantageous embodiment, the method comprises a structured selective application of the active substance regions to the carrier substrate.

• – Aufbringen einer Wirkstoffschicht auf das Trägersubstrat,
• – ausgehend von der Wirkstoffschicht, Strukturieren der Mehrzahl von Wirkstoffbereichen mittels fotolithografischer Maskierungs- und Ätztechniken.

According to an advantageous embodiment, the application of the plurality of active substance areas to the carrier substrate comprises the following:

• Applying a drug layer to the carrier substrate,
• Starting from the drug layer, structuring the plurality of drug domains using photolithographic masking and etching techniques.

According to an advantageous embodiment, the surface of the active substance areas is roughened, whereby an enlarged effective surface for the release of active ingredient arises.

According to an advantageous embodiment, the surface of the active substance areas is roughened, wherein an enlarged effective surface for drug delivery arises, wherein the roughening takes place by etching.

According to an advantageous embodiment, the semipermeable cover layer is a polyparylene layer which is applied by chemical vapor deposition of parylene material.

According to an advantageous embodiment, the active substance regions and the non-active ingredient-containing intermediate regions are structured by wet-chemical polymerization, in particular by a sol-gel process, wherein sol regions formed in the sol-gel process function as active substance regions, and wherein in the sol-gel process Gel areas act as non-active intermediate areas.

The invention will be further described with reference to several embodiments shown in the drawings. Show it

1A . 1B the construction of a layer structure for the delivery of active substances;

2A - 2C a process for producing a layered structure for delivery of active substances;

3 a vapor deposition apparatus which is suitable for applying a semipermeable cover layer;

4A the structure of a parylene dimer;

4B the structure of a parylene monomer;

4C the structure of polyparylene;

5A - 5F a process for producing a layered structure in which the active substance areas are structured by means of photolithographic process;

6A - 6D a further method for producing a layer structure in which recesses are provided in the carrier substrate for receiving the active ingredient material;

7A . 7B the use of a gel sol process to produce a layered structure;

8th a synthetic bubble, the inside of which is provided with a layer structure for the delivery of active substances;

9A . 9B a catheter having a circular inner cross-section, the inside of which is provided with a layer structure for the delivery of active substances; and

10A . 10B a catheter with star-shaped inner cross-section, the inside of which is provided with a layer structure for the delivery of active substances.

In 1 For example, a layered structure according to an embodiment of the present invention is shown in an oblique view. The layered structure is designed to release one (or more) active ingredients continuously with a certain release rate to the outside. The layer structure is on a carrier substrate 100 applied. The carrier substrate can be, for example, polyurethane or silicone, but in addition a large number of other carrier materials are also suitable. On the carrier material 100 There are a variety of drug areas 101 containing the respective active substance (s). The active ingredient may be present as a pure substance (for example silver), but the active ingredient may also be in the form of a suitable galenic preparation on the carrier substrate 100 be upset. The active substance ranges 101 are spaced from each other on the carrier substrate 100 arranged and are by non-active intermediate areas 102 separated from each other. The thickness of the active substance areas 101 typically ranges from about 30 nm up to about 10 μm, with the most preferred thickness range between about 0.1 μm and about 2 μm. The diameter of the drug areas 101 can range from approx. 10 nm up to several millimeters and can thus be varied within a very wide range of values. Typical diameter of the active substance ranges 101 are a few millimeters. The entire surface of the layer system is through a semi-permeable cover layer 103 covered both the drug areas 101 as well as the non-active intermediate areas 102 covers. Due to the semipermeable cover layer 103 will each of the drug areas 101 enclosed on all sides and from above. In this way, a plurality of drug depots is formed, which is completely surrounded by the semipermeable cover layer 103 are enclosed. The semipermeable cover layer 103 is preferably made of polyparylene. The in the drug areas 101 contained active substance can by the semipermeable cover layer 103 to diffuse outward, as indicated by the arrows 104 is shown. The active ingredient is thus delivered continuously to the outside at a defined delivery rate.

At the in 1 In the embodiment shown, the polyparylene adheres directly to the non-active intermediate regions 102 at. Alternatively, an additional primer layer between the carrier substrate 100 and the semi-permeable cover layer 103 be arranged. The thickness of the semipermeable cover layer 103 moves in the range between approx. 30 nm and approx. 10 μm. The thickness of the semipermeable cover layer 103 is chosen so that in the drug areas 101 contained active substance through the semipermeable cover layer 103 can diffuse through to the outside. By the thickness of the semipermeable cover layer 103 is suitably chosen, for the respective active ingredient (or the active ingredients) a desired diffusion rate through the semipermeable cover layer 103 be determined through. By a suitable choice of the thickness of the semipermeable cover layer 103 Thus, the release rate, with which the respective active substance is released to the outside, can be adjusted within wide ranges.

In 1B Fig. 12 is a sectional view through a laminated structure according to embodiments of the present invention. In the sectional image is the carrier substrate 100 with the drug areas applied thereto 101 and the non-active intermediate areas 102 to recognize. In addition, the semipermeable cover layer 103 to recognize both the drug areas 101 as well as the non-active intermediate areas 102 covering to the outside. It can be seen that the semipermeable cover layer 103 in the intermediate areas 102 directly on the carrier substrate 100 adheres, leaving the drug areas 101 all around the side and from the top of the semipermeable cover layer 103 are enclosed. In this way, a plurality of on the surface of the carrier substrate 100 arranged drug depots formed. The in the drug areas 101 contained active substance can by the semipermeable cover layer 103 to diffuse outward, as indicated by the arrows 104 is shown. The active ingredient is thus delivered continuously to the outside at a defined delivery rate.

For the active ingredient in the drug areas 101 may be, for example, elemental silver. Silver has a microbiological activity and counteracts the colonization of bacteria, viruses, fungi and other microorganisms. Silver is therefore of particular interest for medical applications. In a layered structure whose active substance areas 101 Containing elemental silver, the silver diffuses through the semipermeable cover layer 103 through to the outside and is discharged at a constant rate of discharge to the outside. In this way, a colonization with bacteria, viruses, fungi and other microorganisms can be prevented.

When using elemental silver as an active ingredient, it is advantageous if the Diameter of the active substance areas 101 is below a predetermined maximum diameter. If the semipermeable topcoat 103 is destroyed at one or more areas of the cover layer and silver particles from the drug areas 101 In this way, it is ensured that the silver particles are not larger than a predetermined maximum diameter. This is very important, especially in medical applications, since the free floating silver particles could otherwise cause damage to health.

Instead of silver or in addition to silver, the drug areas 101 a microbiologically active substance, an antibacterial substance, an antibiotic, a fungicide or an immunosuppressant as the active ingredient, wherein the respective active ingredient through the semipermeable cover layer 103 is discharged through at a constant rate of discharge to the outside. An example of an immunosuppressant would be rapamycin, which is used to suppress a rejection response of the body. Molybdenum trioxide (MoO ₃ ) would also be mentioned as an example of an antibacterial substance.

With regard to the geometric design of in 1A and 1B shown layer structure, it is advantageous if the width of the non-active areas 102 not too big. The width of the non-active intermediate areas 102 should be chosen so small that the active ingredient in the drug areas 101 through the semipermeable cover layer 103 diffused outwards, evenly reaching all areas of the surface. This should be the non-active intermediate area 102 are chosen so small that the drug from each drug depot at least until the middle of the non-active intermediate area 102 can diffuse. In this way, a uniform release of active ingredient is achieved over the entire surface of the layer structure.

The in the 1A and 1B shown layer structure can be used for both medical and non-medical applications. For example, it is possible to use the inside of a catheter or a ureteral splint with the in 1A or 1B to provide layer structure shown, wherein as active ingredient a microbiologically active substance, an antibacterial substance, an antibiotic, a fungicide or an immunosuppressive agent is used. In particular, the use of silver as the active ingredient can prevent colonization of bacteria, viruses, algae, fungi and other microorganisms in the catheter or in the ureteral splint over longer periods of time. Another medical application involves an alloplastic bladder that can completely replace a patient's bladder. Such a synthetic bubble is made of polyurethane or silicone material. By coating the inside of such a synthetic bubble with the in 1A and 1B The layer structure shown can be achieved that a microbiologically active agent, such as silver, is discharged for a long time at a constant rate of release into the interior of the bladder. In this way, for example, an attack with bacteria, viruses, algae, fungi and other microorganisms can be prevented.

In addition to these medical applications, a number of other applications are conceivable in which it is exploited in particular that colonization with germs and harmful pathogens, ie, for example, with bacteria, viruses, algae, fungi and other microorganisms, are prevented by the continuous, longer-term release of an active substance can. One can think of door handles, bars and handles in public spaces, which are touched daily by a large number of people. In addition, an application of the layer structure in the sheathing of cables in question. Here, for example, a microbiologically active substance (for example, a fungicide) could be used as the active ingredient to prevent the colonization of algae, fungi, mold and other microorganisms on the surface of the cable sheath.

In the 2A to 2C an example of a manufacturing method is shown with which a layer structure of the in 1A and 1B shown type can be produced.

2A shows the substrate 200 to which a number of drug areas are to be applied. At the substrate 200 it may be, for example, polyurethane or silicone.

In 2 B is shown as a variety of drug areas 201 on the substrate 200 is applied. The active substance ranges 201 may contain one or more active substances. The active substance (s) can either be applied in pure form (eg in the form of elemental silver) or applied in a preparation together with excipients.

For applying the active substance areas 201 Depending on the nature of the substances to be applied, a large number of different techniques and methods come into question, starting with galvanic deposition via cathode sputtering or sputtering, in which high-energy ions are shot at a target, to more classical techniques such as vapor deposition, spraying or spin-coating of the respective substances. In addition, PVD (Physical Vapor Deposition) and CVD (Chemical Vapor Deposition) processes are also suitable for applying the active substance ranges. Another possibility is to apply the substances to be applied by means of a printing technique similar to the inkjet printing at the desired locations on the substrate. Printing in particular has the advantage that the active substance regions can be printed in a targeted manner at the desired locations of the substrate, while the intermediate regions which are not active-substance-occupied 202 remain unprinted. Another possibility is the separation of the active substance areas 201 from a suitable reaction solution. For example, areas of elemental silver may be formed by means of a so-called Tollens reaction on the carrier substrate 200 be deposited. As a so-called "Tollens reagent" can be used, for example, a silver nitrate solution, which with the carrier substrate 200 is brought into contact. This silver nitrate solution then becomes areas of elemental silver on the carrier substrate 200 deposited.

The above list of techniques for applying the drug areas 201 on the substrate 200 is merely exemplary and not exhaustive.

In the in the 2A to 2C The methods described should be the active substance ranges 201 only at the designated locations of the substrate 200 be applied while the intermediate areas 202 remain free and not be occupied with active substance. In many of the above-mentioned techniques, it can be achieved by means of a shadow mask that the active substance (or the active ingredients) is applied to the substrate only at the areas provided for this purpose 200 is applied. The intermediate areas 202 are covered during the application of the drug through the shadow mask and are therefore not covered with active ingredient. In this respect, in processes such as cathode sputtering or sputtering, vapor deposition, spraying or structuring with PVD or CVD processes, it is possible to achieve the active substance ranges 201 only at the designated locations of the substrate 200 be formed.

In the last procedural step, in 2C shown is on both the drug areas 201 as well as on the non-active intermediate areas 202 a semipermeable cover layer 203 applied. This will be the drug areas 201 from above and from the sides all around of the semipermeable cover layer 203 surrounded, so that completed drug depots are formed by the semipermeable cover layer 203 completed against the outer medium. Therefore, in the drug areas 201 contained drug first by the semipermeable coating 203 diffuse through to get outside.

The semipermeable cover layer preferably exists 203 from polyparylen. In the coating process, the parylene has a high degree of splitting and is therefore able to form a continuous and uniform layer even on irregular surface structures. For example, a parylene coating is used to insulate and protect electronic components and assemblies from corrosion. In addition, parylene has a great importance in medical technology, because parylene is biocompatible and is characterized by a high compatibility with the body's own tissue. In this respect, implants, aids and prostheses, which are in long-term contact with human tissue, provided with a parylene coating, so as to increase the tolerability. For example, artificial urinary bladders, catheters, and ureteral tracts that remain in the human body for a long time may be provided with a polyparylene coating to improve body compatibility.

According to an advantageous embodiment, the surface of the active substance areas 201 roughened before applying the polyparylene layer. For this purpose, the surface of the active substance areas 201 For example, be etched by means of an etchant to produce in this way a certain micro-roughness of the surface. Roughening increases the effective surface area for drug delivery. Since the parylene has a very high fissuring property, the applied polyparylene layer can be roughened at the surface of the active agent areas 201 follow with high accuracy. The microroughness on the surface of the active substance areas 201 Therefore, it continues to the surface of the polyparylene layer so that consequently also the polyparylene layer has a corresponding surface roughness. The microroughness of the surface influences the wetting properties of the surface. For example, the microroughness of the surface may cause a drop of water to bead off the surface due to the lotus effect without wetting the surface. By a suitable modification of the surface roughness of the active substance ranges 201 Therefore, the surface properties and in particular the wetting properties of the layer structure can be influenced.

In 3 a vapor deposition apparatus is shown with which a polyparylene layer can be applied to a surface to be coated. The vapor deposition apparatus comprises a vacuum recipient 300 in which the vapor deposition process is carried out. Inside the vacuum recipient 300 During the vapor deposition process, a pressure preferably prevails in the range of the fine vacuum, for example in the range between 0.5 Pa and 50 Pa.

In the vacuum recipient 300 gas should preferably be a process gas such. As argon act. The use of a process gas has the advantage over the use of air that there can be no undesirable reactions with the atmospheric oxygen. The process gas is the vacuum recipient 300 via a gas supply line 301 fed, the gas supply by means of a controllable gas valve 302 can be adjusted.

The evacuation of the vacuum recipient 300 via a gas discharge line 303 that the vacuum recipient 300 with a cold trap 304 and with a vacuum pump 305 combines. In the gas discharge line 303 there is a controllable exhaust valve 306 , with which the pumped gas flow can be regulated. The cold trap 304 is intended to condense the vaporized material in the pumped gas so that it does not go to the vacuum pump 305 can get. For this, the walls of the cold trap 304 cooled down to -80 ° C, for example.

At the vacuum pump 305 can it be z. B. may be a mechanically operating vacuum pump, for example, a rotary vane pump. By means of a rotary vane pump can within the vacuum recipient 300 the required fine vacuum in the range of 0.5 Pa to 50 Pa are generated.

For evaporation of the parylene material is within the vacuum recipient 300 a heatable evaporator unit 307 which is often referred to as a "boat". The parylene material 308 is through the evaporator unit 307 heated and evaporated. The evaporator unit 307 can preferably be heated by means of an electrical resistance heater, wherein the resistance heating within the vacuum recipient 300 can be arranged. The resistance heating can also be outside the vacuum recipient 300 be arranged, in which case a good thermal conductivity between the resistance heater and the evaporator unit 307 must be provided.

Alternatively, the heating and evaporation of the vapor deposition material 308 using the Rapid Thermal Processing (RTP) process. In this process, the evaporation material to be vaporized 308 heated by the radiation powerful thermal radiator (for example, halogen lamps).

The parylene material 308 in the evaporator unit 307 is initially in the form of dimers. To start the polymerization, it is necessary to break up the dimers into two reactive monomers. This happens in a so-called pyrolysis unit 309 , When the vaporized parylene material passes through the pyrolysis unit 309 flows through, the dimers are influenced by the inside of the pyrolysis 309 ruling high temperature broken into reactive monomers. After flowing through the pyrolysis unit 309 For example, parylene is almost entirely in the form of parylene monomers.

Inside the vacuum recipient 300 is also the substrate to be coated 310 , During the vapor deposition process, the parylene condenses after passing through the pyrolysis unit 309 is present almost completely in the form of parylene monomers, on the substrate to be coated 310 , There, the highly reactive parylene monomers react to polyparylenketten. In this way, a continuous polyparylene layer is produced on the substrate.

The chemical structure of parylene is in the 4A to 4C shown. 4A shows the originally present dimer of parylene, which consists of two interconnected via the C atoms parylene monomers. In the evaporator unit 307 Parylene is initially in the form of dimers.

Various types of parylene are known, which differ by one or more substitutions of chemical groups on the ring or on the bridge. In the following, "Parylen" is used as a collective term for all variants of parylene.

When the vaporized dimerary parylene passes through the pyrolysis unit 309 flows through, the dimer is broken into two reactive monomers. The chemical structure of the monomer is in 4B shown.

During the coating process, the parylene condenses on the substrate to be coated, and the highly reactive parylene monomers react to form polyparyl chains. In 4C the chemical structure of a polyparyl chain formed from n monomers is shown.

In the 5A to 5F A further production method for a layer structure according to the starting forms of the present invention is shown, in which case photolithographic techniques for structuring the active substance areas are used.

5A shows the carrier substrate 500 , which may for example consist of polyurethane or silicone. In 5B is shown as on the carrier substrate 500 a continuous drug layer 501 is applied. The active ingredient layer 501 may consist of the active substance or the active substances in pure form (for example, silver), but it may also consist of a preparation of the at least one active ingredient together with excipients. The thickness of the drug layer 501 can, for example, move in the range between 30 nm and 10 μm. Depending on the type of active ingredient used come for the application of the drug layer 501 For example, the following methods are considered: electroplating, sputtering or sputtering, vapor deposition, immersing the carrier substrate in a drug solution, spraying, spin-coating, knife-coating of the active ingredient, printing with the active ingredient. In addition, come to apply the drug layer 501 Also PVD (Physical Vapor Deposition) processes and CVD (Chemical Vapor Deposition) processes into consideration. Another possibility, which is particularly important for the application of a silver layer, is the deposition of the active substance layer 501 from a suitable reaction solution. For example, a layer of elemental silver by means of a so-called Tollens reaction on the carrier substrate 500 be deposited. As a so-called "Tollens reagent" can be used, for example, a silver nitrate solution, which with the carrier substrate 500 is brought into contact. From this silver nitrate solution is then a layer of elemental silver on the carrier substrate 500 deposited.

In the following steps will be the drug layer 501 structured suitably by means of a photolithographic process. For this purpose, a photoresist layer is first applied to the active substance layer 501 applied. The photoresist layer is exposed by means of a photomask and then developed. The result is in 5C shown. The exposed and developed photoresist structures 502 cover the underlying drug layer 501 from. In the subsequent etching step, therefore, the drug layer remains 501 below the photoresist structures 502 whereas the drug layer 501 in areas not covered by photoresist 503 is etched away.

The result of the etching process is in 5D shown. In 5D are the photoresist structures 502 together with the underlying drug areas 504 to recognize. The photoresist structures 502 are then removed by means of a suitable solvent. So you get the in 5E shown structure. On the carrier substrate 500 are now both drug areas 504 as well as non-active intermediate areas 505 arranged.

In the last step becomes a semipermeable cover layer 506 on the in 5E applied layer structure shown. Preferably, it is used as a semipermeable cover layer 506 a polyparylene layer is applied, which, for example, with the aid of in 3 can be applied. In 5F the finished layer structure is shown. Each of the active ingredient areas 504 is all around from the side and from the top of the semi-permeable cover layer 506 enclosed. The layer structure is designed to deliver the active substance or active substances to the outside in accordance with predefined release rates. The use of photolithographic processes results in a precise structuring of the active substance areas 504 allows.

In the 6A to 6D a further embodiment of a layer structure is shown in which recesses are provided in the carrier substrate at the active substance areas, into which the active substance is introduced. In contrast to the embodiments described so far, a flat surface can be achieved in this way.

The process for producing this layered structure is disclosed in U.S. Patent Nos. 4,378,378 and 4,605,842 6A to 6D shown. A carrier substrate 600 , this in 6A is shown serves as a starting point for the process. As in 6B is shown, are now at those areas where the drug is applied later, corresponding wells 601 in the surface of the carrier substrate 600 generated. The wells 601 can be generated, for example, by means of an embossing process, wherein an imprint stamp with high pressure against the surface of the carrier substrate 600 is pressed. During pressing, the surface structure of the imprint stamp on the carrier substrate 600 transfer. Another way to create the wells 601 is the removal of material by means of a powerful laser. By laser ablation, the wells can 601 be structured with high precision. Another option is the wells 601 by means of a photolithographic process and a subsequent etching step from the carrier substrate 600 to etch out.

After the wells 601 on the surface of the carrier substrate 600 are generated, the wells are filled with the active ingredient (s). In this case, the active substance or the active substances can be used in pure form (eg in the form of elemental silver). Alternatively, the at least one active ingredient can also be used in a preparation together with excipients. In 6C is shown as the wells 601 be filled with drug material so that drug areas 602 be formed. The active substance ranges 602 are due to non-active intermediate areas 603 separated from each other.

By filling the wells 601 with active ingredient material creates a substantially planar surface. Optionally, an additional polishing or planarization step may be provided to obtain a completely planar surface of the layered structure.

The last step will be on the in 6C Layer structure shown a semipermeable cover layer 604 applied. The semipermeable cover layer is preferably used 604 around a polyparylene layer. The polyparylene layer may be, for example, by means of in 3 be applied vapor deposition apparatus shown. The semipermeable cover layer 604 preferably has a thickness in the range of about 30 nm to 10 microns, wherein the appropriate thickness of the semipermeable cover layer is selected depending on the desired release rate with which the active ingredient is to be discharged to the outside. The semipermeable cover layer 604 covers both the drug areas 602 as well as the non-active intermediate areas 603 , where the drug areas 602 completely surrounded by the semipermeable cover layer 604 be covered. Therefore, the active ingredient needs to go through the semipermeable topcoat to get to the outside 604 diffuse through.

Based on 7A and 7B a further embodiment is shown in which by means of a gel-sol transition, a layer structure according to the invention is prepared. For this purpose, a suitable reaction solution is applied to the surface of a carrier substrate. By a suitable choice of the framework conditions, it can be achieved that a gel-sol transition takes place in the reaction solution. In this case, on the surface of the carrier substrate in 7A formed structure in which a network of polymerized gel strands 700 arises. The gel strand 700 enclose free sol areas 701 , In a next step, the free sol areas 701 Now be filled with at least one suitable drug. The polymerized gel strand 700 act as non-active occupied intermediate areas, which are the drug-occupied sol areas 701 separate each other.

After structuring the gel sol areas and introducing the at least one active substance, a semipermeable cover layer is applied to the in 7A applied sol-gel network applied. In this way, it is possible to form a layer structure in which the structuring of the active substance areas and of the intermediate areas which are not occupied by active substances takes place with the aid of a gel sol process.

In 7B Fig. 3 is a cross-section through a layered structure created by a gel sol process. The layer structure comprises a carrier substrate 702 , on the surface of which a gel-sol network is arranged. The gel-sol network comprises the polymerized gel strands 700 as well as the sol areas 701 that of the gelstrands 700 be enclosed. The active substance is located in the sol areas 701 , Both the polymerized gel strand 700 as well as the drug-occupied sol areas 701 be from the semi-permeable cover layer 703 covered. To get to the outside, must be in the free sol areas 701 contained active substance through the semipermeable cover layer 703 through to the outside.

A layered structure according to embodiments of the present invention is suitable for both medical and non-medical applications where it is necessary to deliver one or more active agents to the surrounding medium for prolonged periods of time at a consistent delivery rate. An important example of a medical application would be an artificial bladder permanently implanted in a patient as a replacement for his natural bladder. In this case, however, bacteria, viruses, fungi and other microorganisms can settle and multiply, in particular in the bladder interior, which can lead to inflammation and complications. Such a settlement can be counteracted by equipping the inner wall of the artificial bubble with a layered structure according to embodiments of the present invention. The layer structure preferably contains agent depots of elemental silver. It is known that silver has a microbiological activity, in particular has an antibacterial effect and can prevent the colonization of bacteria, viruses, fungi and other microorganisms. The silver-coated areas are then covered by a polyparylene layer whose thickness is such that the silver is released over long periods of time at a constant rate of release into the urine contained in the artificial bladder.

A first possibility for structuring the silver-covered areas is to structure them inside the artificial bubble. A second possibility is to put the interior of the art bubble outward and then apply the silver-covered areas. This is in 8th shown. 8th shows the inside turned inside out 800 a synthetic bubble, which may for example consist of polyurethane or silicone. At the areas 801 each elemental silver is applied to the substrate with a thickness of about 30 nm to 10 microns. The intermediate areas 802 however, are not covered with silver. After structuring the silver-coated areas 801 a polyparylene layer is applied to the inside of the synthetic bubble which has been turned outwards and which covers both the silver-coated areas 801 as well as the intermediate areas 802 covered. The polyparylene layer can be applied, for example, by means of a vapor deposition device, as used in US Pat 3 is shown. After application of the polyparylene layer, the artificial bubble is everted again, so that the layer structure is now located on the inside of the artificial bubble. After implantation of the artificial bladder, the layer structure can deliver a constant rate of silver to the urine contained in the artificial bladder for extended periods of time.

Another application in the medical field is the coating of catheters, in particular of bladder catheters. In this case, both the outside and the inside of the catheter for the attachment of an active substance-releasing layer structure comes into question. For example, a coating attached to the exterior of the catheter may serve to deliver one or more agents that enhance the biocompatibility of the catheter and prevent infection in the ureter. An active ingredient-releasing layer structure applied inside the ureter can serve to prevent colonization of the bladder catheter with bacteria, viruses, fungi and other microorganisms. It is also possible to equip both the inside and the outside of the catheter with different active ingredient-dispensing coatings. It is advantageous if the layer structure located on the outside is designed for a higher release rate than the layer structure located on the inside, because the layer structure on the outside is primarily about preventing infections that occur directly after insertion occur during the inner layer structure, a longer-term microbiological efficacy in the foreground to prevent infestation with bacteria, viruses, fungi and other microorganisms.

In the 9A and 9B such as 10A and 10B is shown with reference to two embodiments, as the inside of a catheter can be equipped with a layer structure according to the embodiments of the present invention. In 9A is a section through a catheter 900 shown, the interior of which has a circular cross-section 901 having. The active ingredient material is in the form of drug pathways 902 applied to the inside of the catheter. The drug pathways 902 extend longitudinally along the inside of the catheter as indicated by 9B can be seen. The drug pathways 902 can be applied for example by means of a suitably shaped doctor blade.

After the drug pathways 902 are applied, the entire interior of the catheter, so both the drug pathways 902 as well as the non-active intermediate areas 903 , with a polyparylene layer 904 Mistake. The in the drug pathways 902 contained drug must now pass through the polyparylene layer 904 diffuse through to enter the interior of the catheter.

In the 10A and 10B is another embodiment of a catheter 1000 shown its interior 1001 is formed star-shaped. The active ingredient material is then pressed into the respective tips of the star-shaped inner cross section by means of a suitably shaped doctor blade. This creates drug pathways 1002 extending in the longitudinal direction of the catheter 1000 extend. This is in 10B clearly visible. Subsequently, throughout the interior 1001 of the catheter 1000 a polyparylene layer 1003 applied to both the drug pathways 1002 as well as the non-active occupied intermediate areas covered. To the inside of the catheter 1000 to get into the drug webs 1002 contained active ingredient through the polyparylene layer 1003 diffuse into the interior of the catheter. In this way it can be achieved that the active ingredient over a longer period of time in the interior 1001 of the catheter 1000 is delivered.

In addition to these medical applications, some non-medical applications should be mentioned. For example, a layered structure according to embodiments of the present invention may be used to provide door handles, handholds, or handrails with a coating that permanently releases an active agent, such as an antibacterial agent. Another field of application would be the coating of cables with a microbiologically active layer structure, wherein the released active substance counteracts a settlement of bacteria, viruses, fungi, algae and other microorganisms. In addition to these applications, a variety of other applications are possible.

Claims (21)

Layer structure for dispensing at least one active substance, wherein the layer structure comprises: a carrier substrate ( 100 ), - a plurality of active substance areas ( 101 ) which are spaced apart on the carrier substrate ( 100 ) and the at least one active ingredient, each of the active substance areas ( 101 ) all around non-active intermediate areas ( 102 ) of the carrier substrate is surrounded, - a semipermeable cover layer ( 103 ) placed on the carrier substrate ( 100 ) and the active substance areas ( 101 ) is applied and both the active substance areas ( 101 ) as well as the non-active intermediate areas ( 102 ) of the carrier substrate, wherein the semipermeable cover layer ( 103 ) in the non-active intermediate areas ( 102 ) directly or indirectly on the carrier substrate ( 100 ), each of the active substance regions ( 101 ) all around laterally and from above from the semipermeable cover layer ( 103 ) is enclosed, so that drug depots form, and - wherein the at least one active ingredient through the semipermeable cover layer ( 103 ) can diffuse outwards. Layer structure according to claim 1, characterized by at least one of the following: the layered structure is designed to deliver the at least one active substance to the outside at a predetermined delivery rate; the layer structure is designed so that the at least one active substance diffuses through the semipermeable cover layer and is released to the outside; the drug areas are applied in the form of a repeating pattern on the carrier substrate; the different active substance areas are separated from one another by the non-active intermediate areas; Each of the active substance areas is completely covered by the semipermeable cover layer. Layer structure according to claim 1 or claim 2, characterized in that the at least one active ingredient comprises at least one of the following: a microbiologically active substance, an antibacterial active substance, an antibiotic, an immunosuppressant, a fungicide, silver, rapamycin, molybdenum trioxide. Layer structure according to one of Claims 1 to 3, characterized in that the semipermeable cover layer is a polyparylene layer. Layer structure according to one of claims 1 to 4, characterized by at least one of the following: the carrier substrate is a carrier substrate on which both the at least one active substance and the semipermeable cover layer are adhered; the carrier substrate is polyurethane; the carrier substrate is silicone; the semipermeable capping layer is a polyparylene layer having a thickness in the range of about 100 nm to 300 nm; the semipermeable cover layer is a polyparylene layer having a thickness in the range of about 30 nm to 10 μm; the drug areas have a thickness in the range of about 30 nm to 10 microns; the active agent areas have a thickness in the range of a few micrometers, preferably about 2 micrometers; each of the drug areas does not exceed a predetermined maximum dimension; the active substance ranges each have a diameter of about 10 nm up to a few millimeters; the active substance areas each have a diameter of a maximum of about 3 mm. Layer structure according to one of claims 1 to 5, characterized by at least one of the following: the semipermeable cover layer is designed so that the at least one active substance can diffuse through at a given diffusion rate; the layer thickness of the semipermeable cover layer is selected such that a desired release rate for the at least one active substance is achieved; the layer thickness of the semipermeable cover layer is selected such that a desired permeability of the semipermeable cover layer is achieved; the layer thickness of the semipermeable cover layer is selected such that a desired diffusion rate of the at least one active substance through the semipermeable cover layer is achieved. Layer structure according to one of claims 1 to 6, characterized by at least one of the following: the width of the non-active occupied intermediate regions between adjacent active substance areas is chosen so large that a reliable adhesion of the semipermeable cover layer is ensured around an active substance area; the semipermeable cover layer also adheres to the non-active substance occupied intermediate regions on the carrier substrate, if in the active substance areas the at least one active ingredient is completely or partially consumed; Expansion and arrangement of the active substance areas are selected such that, when the layer structure is loaded laterally, the mechanical properties are essentially determined by the carrier substrate and the semipermeable covering layer; the active substance areas and the non-active substance occupied intermediate areas are dimensioned such that the at least one active substance is also present in the middle of the non-active ingredient intermediate areas with a sufficiently high concentration; the active substance areas are dimensioned so that active ingredient particles which are possibly dissolved out of the active substance areas in the event of damage to the semipermeable covering layer are sufficiently small and harmless. Layer structure according to one of claims 1 to 7, characterized in that the carrier substrate for forming the active substance regions has a plurality of recesses into which the at least one active substance is introduced. Use of a layered structure according to one of claims 1 to 8 for coating a surface of at least one of: a door handle, a handrail, a handle, a cable, a blister, a catheter, a ureter splint. Art bubble, with the inside ( 800 ) of the synthetic bubble has a layer structure for drug delivery according to one of claims 1 to 8. Catheter ( 900 . 1000 ), wherein at least one of the inside and outside of the catheter ( 900 . 1000 ) has a layer structure for drug delivery according to one of claims 1 to 8. The catheter of claim 11, wherein the inside of the catheter has a drug release layer structure according to any one of claims 1 to 8, and wherein the drug regions are in the form of longitudinal drug pathways on the inside of the catheter. Catheter ( 900 . 1000 ), the inside of which has a layer structure for dispensing at least one active substance, the layer structure comprising: a plurality of active substance regions ( 902 . 1002 ) located on the inside of the catheter ( 900 . 1000 ) are applied and contain the at least one active substance, wherein the active substance areas by non-active substance occupied intermediate areas ( 903 ) are separated from each other, - a semipermeable cover layer ( 904 . 1003 ) placed on the inside of the catheter ( 900 . 1000 ) and the active substance areas ( 902 . 1002 ) and both the active substance areas ( 902 . 1002 ) as well as the non-active intermediate areas ( 903 ) of the carrier substrate, wherein the semipermeable cover layer ( 904 . 1003 ) in the non-active intermediate areas ( 903 ) directly or indirectly on the inside of the catheter ( 900 . 1000 ), wherein the semipermeable cover layer ( 904 . 1003 ) both the active substance areas ( 902 . 1002 ) as well as the non-active intermediate areas ( 903 ), so that drug depots form, and - in the drug areas ( 902 . 1002 ) contained at least one active ingredient through the semipermeable cover layer ( 904 . 1003 ) can diffuse outwards. Catheter according to claim 13, characterized by at least one of the following: the active substance areas are applied in the form of longitudinally extending active substance tracts on the inside of the catheter, wherein the active substance tracts are separated from one another by intermediate areas which are not active substance-occupied; the at least one active ingredient is applied to the inside of the catheter by means of a doctor blade in such a way that active substance tracts extending in the longitudinal direction along the inside of the catheter are formed; the catheter has a round or oval inner cross-section, wherein the at least one active substance is applied to the inside of the catheter by means of a doctor blade in such a way that active substance tracts extending in the longitudinal direction along the inside of the catheter are formed; the catheter has a star-shaped inner cross-section, wherein the at least one active substance is introduced into the tips of the star-shaped inner cross-section such that active substance tracts extending in the longitudinal direction along the inner side of the catheter form; the catheter has a star-shaped inner cross-section, wherein the at least one active substance is doctored into the tips of the star-shaped inner cross-section by means of a doctor blade in such a way that active substance tracts extending in the longitudinal direction along the inner side of the catheter form. A method of structuring a layered structure, the method comprising - applying a plurality of active substance areas ( 201 . 504 . 602 ) on a carrier substrate ( 200 . 500 . 600 ), where the active substance areas ( 201 . 504 . 602 ) contain at least one active substance, and wherein each of the active substance areas ( 201 . 504 . 602 ) all around non-active intermediate areas ( 202 . 505 . 603 ) of the carrier substrate is surrounded, - applying a semipermeable cover layer ( 203 . 506 . 604 ) on the carrier substrate ( 200 . 500 . 600 ) and the active substance areas ( 201 . 504 . 602 ), wherein the semipermeable cover layer ( 203 . 506 . 604 ) both the active substance areas ( 201 . 504 . 602 ) as well as the non-active intermediate areas ( 202 . 505 . 603 ) of the carrier substrate, wherein the semipermeable cover layer ( 203 . 506 . 604 ) in the non-active intermediate areas ( 202 . 505 . 603 ) directly or indirectly on the carrier substrate ( 200 . 500 . 600 ), and wherein each of the active substance regions ( 201 . 504 . 602 ) all around laterally and from above from the semipermeable cover layer ( 203 . 506 . 604 ), so that drug depots form, which are outwardly through the semipermeable cover layer ( 203 . 506 . 604 ), wherein the semipermeable cover layer is designed such that the in the active substance areas ( 201 . 504 . 602 ) contained at least one active ingredient through the semipermeable cover layer ( 203 . 506 . 604 ) can diffuse outwards. The method of claim 15, characterized in that applying the plurality of drug regions to the carrier substrate comprises applying at least one of the following methods: electroplating; - sputtering; - sputtering; - vapor deposition; - Diving; - spraying; - spin-on; - chemical vapor deposition; - physical vapor deposition; - doctoring; - printing; - depositing material from a reaction solution on the carrier substrate; Depositing material from a Tollens reagent on the carrier substrate by means of a Tollens method; Depositing silver from a Tollens reagent on the carrier substrate by a Tollens method. A method according to claim 15 or claim 16, characterized by a structured selective application of the active substance areas on the carrier substrate. Method according to one of claims 15 to 17, characterized in that the application of the plurality of active substance areas on the carrier substrate comprises: - Applying an active substance layer on the carrier substrate, - Starting from the drug layer, structuring the plurality of drug areas by means of photolithographic masking and etching techniques , Method according to one of claims 15 to 18, characterized by at least one of the following: The surface of the active substance areas is roughened, whereby an enlarged effective surface for drug delivery arises; the surface of the drug areas is roughened, resulting in an increased effective surface for drug delivery, wherein the roughening is done by etching. Method according to one of claims 15 to 19, characterized in that it is in the semipermeable cover layer is a Polyparylenschicht which is applied by chemical vapor deposition of parylene material. Method according to one of claims 15 to 19, characterized in that the active substance areas and the intermediate areas not active ingredient are structured by wet-chemical polymerization, in particular by a sol-gel process, wherein in the sol-gel process formed Solbereiche act as drug areas, and wherein gel regions formed in the sol-gel process function as non-active intermediate regions.

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