WO2008061642A2 - Method for the creation of a bioactive surface on the balloon of a balloon catheter - Google Patents

Abstract

Disclosed is a method for creating a bioactive surface on a balloon (3) of a balloon catheter (1). In said method, the external face of the balloon (3) is provided with a surface structure or surface profile, the structured or profiled surface (4) of the balloon (3) is moistened with a solution (6) containing an active substance (7) in a solvent (8) that can be mixed with water (9), said active substance (7) having a maximum solubility of 0.9 mg/ml in distilled water, and the solvent (8) is separated from the active substance (7).

Description

 A method of creating a bioactive surface on the balloon of a balloon catheter

The present invention relates to a method for producing a bioactive surface on the balloon of a balloon catheter. The surface produced by this method is characterized by a uniform drug release, which is due to the solubility of the active ingredient used in the tissue.

The so-called "minimally invasive" procedures are becoming more and more important in the field of medicine, where interventional radiology has become an essential part of the development of minimally invasive techniques and necessary devices It is also used by radiologists in vessels to open them, but conventional procedures often result in thickening of the vessel wall with consequent lumen narrowing in the area of dilation by cell proliferation.

By dispensing the drug from the balloon surface, which may be structured to enhance drug loading and drug delivery, and / or provided with a suitable polymeric coating, this problem can be counteracted.

The invention has for its object to provide an advantageous method for producing a bioactive surface on a balloon of a balloon catheter available. This object is achieved by a method according to claim 1. The dependent claims contain further, advantageous embodiments of the invention. The inventive method for producing a bioactive surface on a balloon of a balloon catheter is characterized in that the surface of the balloon is first provided with a surface structuring or surface profiling. The structured or profiled surface of the balloon is then wetted with a solution of an active ingredient in a water-miscible solvent, wherein the active ingredient has a maximum solubility of 0.9 mg / ml in distilled water. In a last step, the solvent is separated from the active ingredient. By means of the method according to the invention, the balloon surface is provided with a layer of noncovalently bound active substance molecules. In this way, drug delivery from the balloon into the tissue is not affected by a polymer coating possibly on the balloon, but depends essentially on the solubility of the drugs in the tissue. By structuring or profiling the surface, in this case the usable surface area for the drug loading is increased, so that a larger drug reservoir is formed than with an unstructured or unprofiled surface.

The surface of the balloon can be structured or profiled, for example, mechanically, thermally or chemically. In particular, the surface can be structured or profiled by roughening. Advantageously, by enlarging the surface of the balloon on the surface, depressions having a depth of 5-50 μm and a width of 5-50 μm are produced.

The active substances used may be substantially water-insoluble or only sparingly soluble in water. Water-insoluble in this context describes substances having a solubility of less than 0.1 mg / ml in distilled water at 25 ° C, and sparingly soluble active substances include substances having a solubility of 0.1-0.9 mg / ml in distilled water. Tretinoin and / or tretinoin derivatives and / or orphan receptor agonists and / or elafinder derivatives and / or corticosteroids and / or steroid hormones and / or paclitaxel and / or taxol and / or taxol derivatives and / or Rapamune and / or tacrolimus and / or hydrophobic proteins and / or cell proliferation-altering substances. As steroid hormones in particular methylprednisolone, dexamethasone or estradiol can be used. Of course, other cell proliferation-altering substances which are insoluble or sparingly soluble in water may also be used as the active ingredient.

As the water-miscible solvent, for example, dimethylsulfoxide (DMSO), dioxane, dimethylformamide (DMF) or tetrahydrofuran (THF) can be used.

The roughened surface of the balloon may be wetted, for example, by dipping, spraying or pipetting with a solution of the active ingredient in the water-miscible solvent.

Advantageously, the solvent can then be separated from the active ingredient by dipping the wetted balloon in water, wherein the water-insoluble active ingredient precipitates and partially deposits on the surface. The solvent is removed during the deposition or precipitation. Alternatively, the solvent may be separated from the drug by allowing the solvent to volatilize.

Furthermore, the surface of the balloon may be functionally coated with a polymer layer prior to formation of the bioactive surface. In this case, the drug can partially store in the polymer layer of the balloon. The thickness of the functional polymer layer may be 10-1000 μm, advantageously 200-400 μm.

The surface of the balloon may be functionally coated, in particular with polyamino-p-xylylene-co-polyoxylylene, prior to the generation of the bioactive surface. To produce a functional polymer layer, monomers in the gas phase can be produced from the starting compounds of the general structures (1), (2) and / or (3) at elevated temperatures and reduced pressures and polymerized by cooling at reduced temperature, with:

(3)

Ri, ₂ , ₃ , 4: in each case, identical or different from one another, hydrogen atoms, halogen atoms, alkyl groups or substituted alkyl groups, aryl groups or substituted aryl groups, organic radicals or radicals, groups of the general structure CO (OMA), metallated groups, hydroxyl groups, amino groups, Carboxyl groups, ester groups, ether groups, acid halide groups, isocyanate groups, sulfur-containing groups, nitrogen-containing groups, phosphorus-containing groups, silicon-containing groups; X ₁ Y: hydrocarbon radicals m: number of repeat units = 1-20 where the temperatures required for the preparation of the monomers are between 500 ^° C. and 1000 ^° C. and the pressures required are less than 500 Pa. Dimers of structure (1) or (2) with m = 2 can be cleaved to monomers at temperatures between 600 ⁰ C and 900 ⁰ C and pressures less than 100 Pa. Subsequently, the polymerization can be carried out at temperatures below 120 ° C.

In the context of the described method, both a single active ingredient and a combination of active ingredients can be deposited on the balloon surface.

The deposition method of the invention differs from other substance coatings in the result of the slow and uniform drug delivery. In these methods, the amount of active ingredient applied depends on the concentration of the active ingredient in the solution.

The inventive method is also characterized by the fact that it is technically easy to carry out and allows a constant release of active ingredient. In addition, since no further processing steps after the

Application of the active substance or substances is necessary, no destruction of the active ingredient, such as by applying a second

Polymer coating, to be feared. Thus, relatively unstable drugs such as tretinoin can be easily applied to the balloon surface.

Further features, properties and advantages of the present invention will be described below by means of embodiments with reference to the accompanying figures.

Fig. 1 shows schematically a balloon catheter.

Fig. 2 shows schematically a section of the roughened and wetted surface of a balloon catheter.

Fig. 3 shows schematically a water-immersed, wetted balloon catheter.

Fig. 4 shows schematically a section of an in-water, roughened and wetted surface of a balloon catheter.

Fig. 5 shows schematically a section of a roughened, coated with an active surface of a balloon catheter.

6 schematically shows a section of a surface of a balloon catheter initially coated with a polymer layer, the polymer layer in turn being coated with an active substance.

In the following, a first embodiment of the invention with reference to Figures 1 to 5 will be explained in more detail. 1 shows schematically a balloon catheter 1, the surface of which by means of a spray device 5 with a solution 6 of an active substance 7 in a water-miscible solvent 8 is sprayed. The balloon catheter 1 comprises a catheter probe 2, which is partially enveloped by a balloon 3. The surface of the balloon 3 was first roughened and thereby structured or profiled. The depressions formed on the surface during roughening are schematically indicated by points 4. This structuring or profiling improves the adhesion or absorption capacity of the active ingredients. Structuring or profiling of the surface can be achieved mechanically, thermally or chemically. The small depressions 4 produced in this case advantageously have a depth of 5-50 μm and a width of 5-50 μm.

FIG. 1 schematically shows a spray device 5, for example a spray bottle, with the aid of which a solution 6 of an active substance 7 in a water-miscible solvent 8 is sprayed onto the roughened surface 4 of the balloon 3. Alternatively, the solution 6 of the active agent 7 may be applied to the roughened surface 4 of the balloon 3 by dipping or pipetting.

The active substance used may be, for example, tretinoin and / or tretinoin derivatives and / or orphan receptor agonists and / or elafinder derivatives and / or corticosteroids and / or steroid hormones and / or paclitaxel and / or taxol and / or taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or cell proliferation-altering substances. The steroid hormones may be, for example, methylprednisolone, dexamethasone or estradiol. As the water-miscible solvent, for example, dimethylsulfoxide (DMSO), dioxane, dimethylformamide (DMF) or tetrahydrofuran (THF) can be used.

FIG. 2 schematically shows a section of the surface 4 of the balloon 3 so wetted. FIG. 2 shows a section through the roughened surface 4 of the balloon 3. On the surface 4 there is a solvent 8 in which an agent 7 is dissolved. The roughened Surface 4 is thus wetted with the dissolved in a solvent 8 active ingredient 7.

The balloon catheter 1, whose balloon surface 4 has been wetted in this way, is then immersed in a water bath. This is shown schematically in FIG. FIG. 3 shows a vessel 10 in which

Water 9 is located. The balloon 3 of the balloon catheter 1 is completely in the

Water 9 has been immersed. The roughened and with a solution of the

Active ingredient wetted in a water-miscible solvent

Surface 11 is thus in direct contact with the water 9 located in the vessel 10.

FIG. 4 schematically shows a section of the surface 4 of the balloon 3 of the balloon catheter 1 located in the water 9. FIG. 4 shows how the active substance 7 deposits on the roughened balloon surface 4 by precipitation. The solvent 8, in which the active substance 7 was initially dissolved, slowly mixes with the water 9 surrounding the surface 4. Since the active ingredient 7 is not or only sparingly soluble in water, it does not mix with the water 9. Instead, it remains he as a coating on the roughened surface 4 of the balloon. 3

FIG. 5 schematically shows a section of the surface 4 of the balloon 3 after the balloon has been removed from the water bath shown in FIG. 3 and the water possibly still remaining on the surface 4 has evaporated. The roughened surface 4 of the balloon 3 is coated exclusively with the active substance 7 in FIG.

Instead of precipitating the active ingredient 7 in a water bath, the solvent 8, after the roughened surface 4 of the balloon 3 was wetted with the solution of the active ingredient 7, also be separated by volatilization of the active ingredient 7. If the solvent 8 has volatilized, then the roughened surface 4 of the balloon 3 is coated exclusively with the active substance 7, as shown schematically in FIG. In the following, a second embodiment of the present invention will be described in detail with reference to FIG. In the present exemplary embodiment, the surface of the balloon 3 of the balloon catheter 1 is first functionally coated with a polymer layer. For this purpose, the balloon 3 of the balloon catheter 1, the dimeric 4-amino- [2,2] -paracyclophane at 700 ⁰ C and 20 Pa is cleaved in reactive monomers, and then polymerized in the third, cooled to about 20 ⁰ C. The surface of the balloon The desired thickness of the polymer coating is advantageously 10-1000 μm, more advantageously 200-400 μm.

The polymer-coated balloon surface is then roughened, as described in more detail in connection with the first embodiment. Subsequently, the roughened surface 4 of the balloon 3 is wetted with tretinoin or tretinoin derivatives dissolved in dimethyl sulfoxide (DMSO). The wetted polymer-coated balloon catheter 1 is then immersed in water as described in more detail in connection with FIGS. 3 and 4. In this case, the water-insoluble active substance 7 precipitates and at least partially deposits on the roughened surface 13 of the polymer coating 12 and / or partially deposits itself in the polymer layer 12. This is shown schematically in FIG. FIG. 6 shows a section of the surface of the balloon 3. It is functionally coated with a polymer layer 12. The polymer layer 12 has a roughened surface 13 on which active substance 7 is located and into which partial active substance 14 has been incorporated.

Alternatively to a precipitation of the active ingredient 7 in water, the solvent 8, after the roughened surface 13 of the polymer layer

12 of the balloon 3 was wetted with the solution of the drug 7, also by volatilization of the drug 7 are separated. If the solvent 8 volatilizes, as a result the roughened is

Surface 13 of the polymer layer 12 of the balloon 3 coated exclusively with the drug 7, as shown schematically in Figure 6.

In the following, further embodiments of the invention will be described in more detail. In the method for producing bioactive surfaces on a balloon of a balloon catheter, the balloon can first with a functionalized polymer layer and then provided with a further active substance-containing layer. The process may be characterized in that for the preparation of the functional polymer layer from the starting compounds of the general structures (1), (2) and / or (3) at elevated temperatures and reduced pressures substantially monomers are generated in the gas phase and these then by cooling be polymerized at reduced temperature with:

(D (2)

(3)

R _n : hydrogen atoms, halogen atoms, alkyl groups or substituted alkyl groups, aryl groups or substituted aryl groups, organic radicals or radicals, groups of the general structure CO (OMA) (with M: aliphatic or aromatic groups and A: eg hydrogen, hydroxyl, amino -, carboxyl groups), metallated groups, hydroxyl groups, amino groups, carboxyl groups, first groups, ether groups, acid halide groups, isocyanate groups, sulfur-containing groups (eg sulfonic acid, thioether, sulfuric acid groups), nitrogen-containing groups (eg nitrile, amide, nitro, nitrosamine) , phosphorus-containing groups (eg phosphoric acid ester, phosphonate groups), silicon-containing groups (eg SiIyI, silyloxy groups)

X, Y: hydrocarbon radicals: for example: methylene, isopropylidene, ethylene groups, functionalized hydrocarbon radicals m: number of repeat units

Depending on the starting compounds used, the temperatures or pressures required for the preparation of the monomers are between 500 and 1000 ^° C. or less than 500 Pa.

The process may be characterized in that dimers of structure (1) or (2) with n = 1 are cleaved to monomers at temperatures between 600 and 900 ⁰ C and pressures below 100 Pa, and the subsequent polymerization at temperatures below 120 ⁰ C. is carried out. In addition, the deposited on the vascular endoprosthesis functional polymer may advantageously have a layer thickness between 10 .mu.m to 1000 .mu.m, more preferably a layer thickness of 200 .mu.m to 400 .mu.m.

For depositing the active ingredient layer, the polymer-coated balloon wetted with a solution of the active ingredient (s) in a water-miscible solvent such as dimethylsulfoxide (DMSO), dioxane, dimethylformamide (DMF) or tetrahydrofuran (THF) may be immersed in water the water-insoluble active ingredient precipitates and partially separates on the surface. Furthermore, hydrophobic and electrostatic interactions with the functional groups of the functional polymer coating can result in higher drug loading and drug adhesion compared to the non-coated surface. In addition, partially store the active substance (s) in the polymer layer. In principle, water-insoluble or sparingly soluble in water active ingredients such as. Tretinoin and tretinoin derivatives, orphan receptor agonists, elafinder derivatives, corticosteroids and steroid hormones (such as methylprednisolone, dexamethasone, estradiol), taxol, taxol derivatives, rapamune, tacrolimus, hydrophobic proteins or cell proliferation-altering agents. The kinetics of drug release can be determined in vivo from the vascular endoprosthesis surface by the poor solubility of the drug or agents in aqueous media.

The active ingredient-containing layer may also be a further polymer layer which is produced by being directly covalent or is covalently bound to the functional polymer coating via a spacer system and then loaded with active ingredient. In this case, the covalently bonded polymer can be a thermosensitive polymer which has an open structure at a temperature below 36 ° C. in the active substance-containing medium, into which active ingredient molecules can be taken up, and a closed one at temperatures> 36 ° C. Has structure in which drug molecules are included. Active substances such as tretinoin and tretinoin derivatives, orphan receptor agonists, elafinder derivatives, corticosteroids and steroid hormones (such as methylprednisolone, dexamethasone, estradiol), taxol, taxol derivatives, rapamune, tacrolimus, hydrophobic proteins or cell proliferation-altering substances can be used.

The method may additionally be characterized in that, for the purpose of depositing the active ingredient layer, the polymer-wetted with a solution of the active substance (s) in a water-miscible solvent such as dimethyl sulfoxide (DMSO), dioxane, dimethylformamide (DMF) or tetrahydrofuran (THF). coated balloon is immersed in water, wherein the water-insoluble active ingredient precipitates and partially separates on the surface. By hydrophobic and electrostatic interactions with the functional groups of the functional polymer coating in this case, a higher drug loading and drug adhesion compared to the non-coated surface can be achieved. The active ingredient (s) may additionally be partially incorporated into the polymer of the balloon. It is possible to use water-insoluble or sparingly water-soluble active substances such as tretinoin and tretinoin derivatives, orphan receptor agonists, elafinder derivatives, corticosteroids and steroid hormones (such as methylprednisolone, dexamethasone, oestradiol), taxol, taxol derivatives, rapamune, tacrolimus, hydrophobic proteins or cell proliferation-altering substances. The kinetics of drug release can be determined in vivo from the vascular endoprosthesis surface by the poor solubility of the drug or agents in aqueous media. The active ingredient-containing layer may also be a further polymer layer which is produced by being covalently bound directly to the functional polymer coating covalently or via a spacer system and subsequently loaded with an active substance or active ingredients. In this case, the covalently bonded polymer can be a thermosensitive polymer which has an open structure at a temperature below 36 ° C. in the active substance-containing medium, into which active ingredient molecules can be taken up, and a closed one at temperatures> 36 ° C. Has structure in which drug molecules are included.

Claims

claims A method for producing a bioactive surface on a balloon (3) of a balloon catheter (1), wherein the outside of the balloon (3) is provided with a surface structuring or surface profiling; the structured or profiled surface (4) of the balloon (3) is wetted with a solution (6) of an active substance (7) in a water-miscible solvent (8), the active substance (7) having a maximum solubility of 0.9 mg / ml in distilled water; and the solvent (8) is separated from the active agent (7). 2. The method of claim 1, wherein the surface of the balloon (3) is mechanically, thermally or chemically structured or profiled. 3. The method of claim 2, wherein the surface of the balloon (3) is structured by profiling or profiled. 4. The method according to any one of claims 1 to 3, wherein by enlarging the surface of the balloon (3) on these depressions with a depth of 5-50 microns and a width of 5-50 microns are generated. 5. The method according to any one of claims 1 to 4, wherein the active ingredient used (7) tretinoin and / or tretinoin derivatives and / or orphan receptor agonists and / or Elafinderivate and / or corticosteroids and / or steroid hormones and / or paclitaxel and / or taxol and / or Taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or cell proliferation-altering substances. 6. The method of claim 5, wherein as steroid hormones methylprednisolone, dexamethasone or estradiol can be used. 7. The method according to any one of claims 1 to 6, wherein as the water-miscible solvent (8) dimethyl sulfoxide (DMSO) ₁ dioxane, dimethylformamide (DMF) or tetrahydrofuran (THF) is used. 8. The method according to any one of claims 1 to 7, wherein the roughened surface (4, 13) of the balloon (3) is wetted by immersion, spraying or pipetting. 9. The method according to any one of claims 1 to 8, wherein the solvent (8) is separated from the active substance (7) by the wetted balloon (3) is immersed in water (9), wherein the water-insoluble Active ingredient (7) fails and partially on the surface (4, 13) separates. 10. The method according to any one of claims 1 to 8, wherein the solvent (8) is separated from the active substance (7) by volatilizing the solvent (8). A method according to any one of claims 1 to 10, wherein the surface of the balloon (3) is functionally coated with a polymer layer (12) prior to formation of the bioactive surface. 12. The method according to claim 11, wherein the thickness of the functional polymer layer (12) is 10-1000 μm. 13. The method of claim 12, wherein the thickness of the functional polymer layer (12) is 200-400 microns. A method according to any one of claims 11 to 13, wherein the surface of the balloon (3) is functionally coated with polyamino-p-xylylene-co-polyoxylylene prior to formation of the bioactive surface. 15. The method according to any one of claims 11 to 14, wherein for the production of a functional polymer layer (12) from the starting compounds of the general structures (1), (2) and / or (3) at elevated temperatures and reduced pressures produces monomers in the gas phase and polymerized by cooling at reduced temperature, with:

(3) Ri, ₂ , ₃ , ₄ : in each case, identical or different from one another, hydrogen atoms, Halogen atoms, alkyl groups or substituted alkyl groups, aryl groups or substituted aryl groups, organic radicals or radicals, groups of the general structure CO (O-M-A), metallated groups, hydroxyl groups, Amino groups, carboxyl groups, ester groups, ether groups, Acid halide groups, isocyanate groups, sulfur-containing groups, nitrogen-containing groups, phosphorus-containing groups, silicon-containing groups; X ₁ Y: hydrocarbon radicals m: number of repeating units = 1-20 where the temperatures required for the preparation of the monomers between 500 ⁰ C and 1000 ⁰ C and the required pressures are less than 500 Pa. 16. The method of claim 15, wherein Dimers of structure (1) or (2) with m = 1 at temperatures between 600 ^c C and 900 ⁰ C and pressures less than 100 Pa are cleaved to monomers, and the subsequent polymerization at temperatures below 12O ⁰ C is performed.