STENT WITH IMMEDIATELY REMOVEABLE COATING

Abstract

The invention concerns an implantable medical device which is coated with a substance. The invention provides for rapid release of the substance.

Claims

1. An implantable medical device, coated with a rapidly releasable substance or substance mixture, comprising a main body with a substance and/or a substance mixture applied to a surface of the main body, wherein the dose of the substance or of the substance mixture is >5 μg/mm.sup.2 with respect to the coated surface area.

2. An implantable medical device, coated with a rapidly releasable substance or substance mixture, for arteriosclerosis-conditioned vascular stenosis, comprising a main body with a substance and/or a substance mixture applied to a surface of the main body, wherein the dose of the substance or of the substance mixture is >5 μg/mm.sup.2 with respect to the coated surface area.

3. The implantable medical device as claimed in claim 1, characterized in that the main body consists of a metal, a synthetic material, a natural product or a combination of these materials, in particular consists of steel, cobalt-chrome and/or a nickel-titanium alloy, and is deformable.

4. The implantable medical device as claimed in claim 1, wherein the medical device only remains implanted for a limited period or during or its position changes in its entirety or in part during or after implantation.

5. The implantable medical device as claimed in claim 1, characterized in that the substance is a taxane, a statin or a mTOR inhibitor or contains this as a mixture with other substances.

6. The implantable medical device as claimed in claim 1, characterized in that the medical device has a lumen, wherein preferably, the lumen contains a balloon which in particular is coated with substance, for the purposes of dilation.

7. The implantable medical device in the form of a stent as claimed in claim 1, characterized in that a balloon coated with substance is located in the lumen of the stent for the purposes of post-dilation.

8. The implantable medical device as claimed in claim 1, which contains at least one further substance which inhibits arteriosclerosis and/or which promotes the regression of arteriosclerotic plaque, in particular statins, and/or which has an antimicrobial action, and/or which inhibits blood clotting and/or which promotes thrombolysis.

9. The implantable medical device as claimed in claim 1, characterized in that the substance is or comprises paclitaxel.

10. The implantable medical device as claimed in claim 1, characterized in that the substance is selected from sirolimus, everolimus, zotarolimus, biolimus and temsirolimus or comprises one of these substances, and/or comprises a substance mixture with one of these substances.

11. The implantable medical device as claimed in claim 1, characterized in that the dose of the substance or substance mixture is >10 μg/mm.sup.2.

12. The implantable medical device as claimed in claim 1, wherein the implantable medical device is or comprises a stent.

13. A method for coating stents and medical devices of a related form, wherein a coating solution for coating a surface of the medical device is used at a low temperature, preferably in the range from approximately 0° C. to minus 20° C.

14. The method for coating stents and medical devices of a related form as claimed in claim 11, wherein the coating solution is applied to the surface with the aid of a volumetric measuring device, preferably a syringe, microsyringe or semi-automatically or completely automatically operated piston syringe.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1A is an illustration of a length of an uncoated stent;

[0040] FIG. 1B is a view as in FIG. 1A with a stent that is dip coated; and

[0041] FIGS. 2-6 are views corresponding to those in FIG. 1B and showing alternative forms of stents.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0042] Medical Devices for the Coating

[0043] Any medical device with a coating which can be coated with rapid-eluting medicinal products in a medically acceptable manner and which is introduced into the body for a short term or permanently is suitable. Metals, synthetic materials or natural products and combinations of products of this type such as stent grafts are suitable as the material. The materials may be plastically or elastically deformable and have shape memory. The surfaces may be smooth, for example polished, or porous or structured or be covered with additional materials.

[0044] Medical products which come into contact with the tissue or lumen to be treated for only a short period, i.e. for seconds to a few hours, are preferred. This encompasses medical devices which are removed shortly after use or for which their position in the body is changed during implantation. Examples are self-expandable or balloon-expandable stents the struts of which are displaced during or shortly after implantation against the vessel wall, for example by expansion/post-dilation. By delivering the substance during this process, sections of the vessel wall are supplied with substance which later have no direct contact with the coated stent struts. Coating of a stent of this type is described in Example 15.

[0045] A further advantage of the immediate medicinal product delivery is that, shortly after first contact with the tissue, the known compatible struts of the stent contain no polymers or other components of the coating which delay the delivery of the medicinal product and could compromise the compatibility of the stent material. The coatings disclosed here with a particularly high medicinal product dose/mm.sup.2 of the surface area of the medical device are particularly advantageous for the very thin-walled and short stents (tacks, which are stents used for spot stenting) which are used only in spots in sections of vessels where balloons alone cannot be sufficiently expanded. These segments of vessel which are difficult to expand mechanically in particular require additional treatment with a drug which inhibits restenosis.

[0046] Particularly preferred medical devices are stents which will be mentioned below by way of an example of other medical devices.

[0047] Medicinal Products, Substances

[0048] In principle, any medicinal products or otherwise pharmacologically effective substances and substance mixtures are suitable. Preferred substances are substances which are slowly released from stents for inhibiting excessive tissue proliferation (for example antineoplastic substances such as paclitaxel and other taxanes as well as sirolimus, everolimus, zotarolimus and other mTOR inhibitors), substances for improving healing, for the inhibition of inflammation, substances which inhibit the advance of processes leading to arteriosclerosis and arteriosclerosis itself, or which promote the regression of arteriosclerotic plaque, such as statins, for example (cerivastatin, atorvastatin, fluvastatin), and substances with an antimicrobial action, or substances for affecting blood clotting, such as heparin and heparin fragments and thrombolytics such as urokinase, streptokinase or recombinant tissue plasmin activators.

[0049] Dose

[0050] The medical devices and methods in accordance with the invention are used for the targeted therapy of spatially narrow, limited diseased regions of the body. By means of the type of administration, locally high concentrations of substance are obtained despite the small quantities of medicinal product, while the load with respect to the body as a whole remains very low.

[0051] The medicinal products are applied to medical devices or are contained in medical devices. When the medical devices make contact with tissue, they are delivered into the body. The dose is with respect to the surface area of the medical device which comes into intimate contact with surfaces within the body, for example arterial walls. This dose on the surface of the medical device in the state of contact with the target tissue is >5 μg of substance or substance mixture/mm.sup.2 after sterilization of the medical device, preferably >10 μg/mm.sup.2 and most preferably >15 μg/mm.sup.2. in the case of stents, these limits also apply to the abluminal faces of the stent struts.

[0052] Liquid Preparations for the Coating

[0053] Stents and other medical devices are coated with paclitaxel (representing a taxane) and/or rapamycin (mTOR inhibitor, macrolide) and/or with other substances, preferably those mentioned above, wherein the medicinal products are partially or completely dissolved or even suspended in an organic solvent which is immiscible or miscible with water or even which contains water. Preferred solvent mixtures contain ≥10% by volume of water, more preferably ≥15% by volume of water, most preferably ≥20% by volume of water. Preferred concentrations are 10-100 mg of substance or substance mixture in one mL of solution. Preferred organic solvents which are miscible with water are methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dioxane, dimethylsulphoxide. These could contain additional solvents which are immiscible with water or which only take up a little water, examples of which are ether, acetic acid ethyl ester, hexane, cyclohexane, heptane, xylene or other related solvents, or even halogen-containing solvents such as chloroform, dichloromethane or trifluoroethanol.

[0054] Application of Medicinal Product to the Medical Device

[0055] The stents or other medical devices may be coated by dipping into the substance solutions. The problem in this regard is that only very little solvent and medicinal product adheres to smooth surfaces. The applied dose of medicinal product was substantially higher at low temperatures, for example at approximately 0° C. to minus 20° C. (Example 1) and/or by repeated dipping and drying (see Example 1, Table 2). Increasing the quantity of the adhering material is surprising, because the substance is soluble in the dipping solution. Overall, more substance was applied than for a clinically effective balloon of the same size (4.0×60 mm) at the usual dose of 3 μg/mm.sup.2 (2261 μg) and at a substantially higher density of the medicinal product (μg/mm.sup.2) on the surface of the medical device (Table 3, right hand column). The coating solution may be sprayed onto the surface. By directed spraying or by means of suitable protective measures, in the case of stents, coating of the post-implantation lumen side (the side directed towards the blood flow) surfaces of the stent can be avoided.

[0056] Despite the very delicate form of the stent (see FIGS. 1-6), a defined volume of a coating solution was successfully applied onto the stent surface by means of a microsyringe.

[0057] After coating with a liquid preparation, the medical devices are dried.

[0058] Preparation of Coated Stents and Comparable Medical Devices for Introduction into Arteries or Other Ducts or Tissues

[0059] Stents and comparable medical devices (for example balloon catheters) have to be reduced to as small a diameter as possible for introduction into the body. To this end, for example, the diameters of self-expandable stents are compressed and pushed or pulled into narrow tubes. Transfer of the product from the expanded state into an application catheter is facilitated by using a funnel-shaped introduction aid.

[0060] Balloons which have been coated in the expanded, inflated state are folded after coating or, insofar as they were folded before coating, they are re-folded, for example by applying a vacuum, and stored in a removable protective sheath. Deformation of the coated structure and rubbing together of the structures both at the tube entrance and in the lumen of the tube cause a loss of coating and/or of medicinal product.

[0061] The products for use in patients are sterile. They are preferably sterilized using ethylene oxide; other methods are possible, such as production and packaging under sterile conditions or heat or radiation sterilization.

[0062] Application

[0063] The coated medical devices are brought to the place of use in the body in as minimally invasive a manner as possible and deployed or inflated there. Shortly after elution of a therapeutically or prophylactically effective dose of a substance, they are removed, their position is changed completely or in part, or they are left implanted. The desired effect is also obtained when the implant is in contact with the tissue which is to be treated therapeutically or tissue in its near vicinity for only a short time.

Example 1

[0064] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation

[0065] Coating solutions: tetrahydrofuran/water 60/40 V/V, 20 mg paclitaxel/mL or ethanol/tetrahydrofuran/water 60/20/20 V/V/V, 20 mg paclitaxel/mL.

[0066] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717 or paras 1-3); total surface area of a stent: 188.5 mm.sup.2, by briefly being dipped into the coating solution 8 times. For each layer, the stents were dipped in the solution for 1 sec and then dried for 20 sec in a stream of air at 50° C.

TABLE-US-00002 TABLE 2 Paclitaxel onto the coated stents, THF = tetrahydrofuran THF/water Ethanol/THF/water Coating solution 60:40 (V/V) 60:20:20 (V/V/V) Temperature Room temperature −20° C. Stent 1 193 μg 860 μg Stent 2 171 μg 886 μg Mean 182 μg 873 μg

Example 2

[0067] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation

[0068] Coating solution: ethanol/acetone/water 40/40/20 V/V/V, 30 mg paclitaxel/mL.

[0069] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent: 188.5 mm.sup.2, by briefly being dipped into the cooled coating solution (−20° C.) 10 times. For each layer, the stents were dipped in the solution for 1 sec and then dried for 20 sec in a stream of air at 50° C.

TABLE-US-00003 TABLE 3 Medicinal product content of coated stents, comparison with angioplasty balloons Dimensions: Surface area Paclitaxel on the stent 4.0 × 60 mm Sample mm.sup.2 [μg] [μg/mm.sup.2] Stents, 10 × RF-3V3- 188.5 2782 14.8 dip-coated 1 1 RF-3V3- 188.5 3336 17.7 3 Coated angioplasty — 810 2850 3.5 balloon for comparison

[0070] The balloon (clinically tested, effective product) was coated with 3.5 μg paclitaxel/mm.sup.2, in total approximately 2850 μg of paclitaxel. In Example 2, Table 3, it can be seen that almost the same dose was successfully deposited onto a substantially smaller surface area.

[0071] FIG. 1 in this regard shows, in FIG. 1A, an uncoated stent and in FIG. 1B, a stent which has been dip coated, what is known as a spike stent. Conclusion: despite the small surface area of the stent, it was possible to provide a coat with a dose of similar amplitude on the vessel surface to be treated (defined by the diameter and length of the vessel to be treated) as with a coated balloon catheter.

Example 3

[0072] Influence of Repeated Dipping and Drying on the Dose on the Stent

[0073] Coating solutions: [0074] (a) ethanol/tetrahydrofuran/water (60/20/20), 20 mg paclitaxel/mL [0075] (b) ethanol/acetone/water (40/40/20 V/V/V), 30 mg paclitaxel/mL

[0076] Stents as described in Example 1 were coated by brief repeated dipping into cooled coating solutions (−20° C.) coating solutions. For each layer, the stents were dipped in the solution for 1 sec and then dried for 20 sec in a stream of air at 50° C.

TABLE-US-00004 TABLE 4 Coating of stents by repeated dipping into solutions of medicinal products, paclitaxel content of stents; influence of repetition of coating on the medicinal product content of the stents Coating solution: ethanol/ Coating solution: tetrahydrofuran/ ethanol/acetone/ water (60/20/20), water (40/40/20), 20 mg paclitaxel/mL 30 mg paclitaxel/mL Coated Dose Coated quantity Coating quantity of [μg/mm.sup.2 stent of paclitaxel Dose cycles paclitaxel [μg] surface area] [μg] [μg/mm.sup.2] 2 275 1.46 372 1.97 4 588 3.12 745 3.95 6 662 3.51 1059 5.62 8 788 4.18 1732 9.19 10 1104 5.86 2536 13.45

[0077] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717) by brief repeated dipping into cooled coating solutions. “Coating cycle” means that the stents were dipped into the solution for 1 second and then dried for 20 sec in a stream of air at 50° C.

[0078] The entire surface area of the stent was 188.5 mm.sup.2 and was therefore substantially smaller than the surface area of the correspondingly dimensioned balloon (810 mm.sup.2).

Example 4

[0079] Loss of Medicinal Product During the Introduction of Coated Stents into the Catheter Provided for Administration Through a Tapered Channel

[0080] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717) by brief repeated dipping into cooled coating solutions. “Coating cycle” means that the stents were dipped into the solution cooled to −20° C. for 1 second and then dried for 20 sec in a stream of air at 50° C. Eight coating cycles were carried out.

[0081] Coating solution: ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water was 20% by volume. The paclitaxel concentration in the coating solution was 24 mg/mL.

TABLE-US-00005 TABLE 5 Paclitaxel on the stents after dip coating eight times Paclitaxel content directly after Sample coating [μg] RF3b2-1 1711 RF3b2-4 1423 RF3b2-7 1547 Mean ± SD 1560 ± 145

[0082] The coated stents were compressed to a small diameter by passage through a stainless steel block with tapered holes and then introduced into the lumen of the application catheter; the paclitaxel content of the flattened particles was determined. These particles contained a total (n=6) of only 0.42±0.37% of the medicinal product dose on the stent.

TABLE-US-00006 TABLE 6 Loss of coating during compression of the stent and introduction into the application catheter Paclitaxel loss % of paclitaxel dose Sample name [μg] (Table 5) RF-3b2-2 load 3.8 0.24 RF-3b2-3 load 13.7 0.88 RF-3b2-5 load 4.0 0.26 RF-3b2-6 load 1.2 0.08 RF-3b2-8 load 14.4 0.92 RF-3b2-9 load 3.0 0.19 Mean ± SD 6.7 ± 5.8 0.42 ± 0.37

[0083] Dip coating: paclitaxel 24 mg/mL ethanol/acetone/water 40/40/20 V/V/V.

Example 5

[0084] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation with a Measured Volume of Coating Solution

[0085] Coating solution (a): ethanol/acetone/water or (b): ethanol/THF/water, wherein the proportion of ethanol was respectively 40% by volume, the proportion of acetone or THF was 40% or 50% by volume and the proportion of water corresponded to 20% or 10% by volume. The paclitaxel concentration in the coating solution was 12.5 mg/mL. Coating was carried out by rotation of the medical device (21 rpm) and using a Hamilton microsyringe with a volume of 75 μL/stent (4.0×60 mm). 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent=188.5 mm.sup.2, by distributing the solution over the irregular surface of the stent.

[0086] Using this method also produced an unexpectedly uniform, white coating on the silver-grey metallic stent.

[0087] The stent shown in FIG. 2 has a coating. This was applied by means of a RF—3d coating solution (paclitaxel 12.5 mg/mL ethanol/acetone/water 40/50/10 V/V/V, applied by means of a Hamilton syringe.

TABLE-US-00007 TABLE 7 Paclitaxel on the stents after introduction into the application system (compression of stent, storage in narrow-lumen tube) and subsequent deployment Paclitaxel in Paclitaxel on catheter with stent deployed stents Sample [μg] Mean ± SD Sample [μg] Mean ± SD RF-sd3c-1 1333 1259 ± 149 RF- 1033 1223 ± 118 s4a-1 RF-sd3c-2 1128 RF- 1175 s4a-2 RF-sd3c-3 1337 RF- 1237 s4a-3 RF-sd3d-1 1422 RF- 1331 s4a-1 RF-sd3d-2 1075 RE- 1203 s4a-2 RF-sd3d-3 No value RF- 1361 s4a-3

Example 6

[0088] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation with a Measured Volume of the Coating Solution

[0089] Coating solution: ethanol/acetone/THF/water, wherein the proportions of ethanol, acetone and THF were respectively 30% by volume and the proportion of water corresponded to 10% by volume. The paclitaxel concentration in the coating solution was 20 mg/mL. Coating was carried out by rotation of the medical device (21 rpm) and using a Hamilton microsyringe with a volume of 75 μL/per stent (4.0×60 mm).

[0090] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent=188.5 mm.sup.2, by distributing the solution over the irregular surface of the stent.

[0091] FIG. 3, like FIG. 2, shows a photographic image of a portion of a coated stent. For the coating, a RF-G-20 coating solution (paclitaxel 20 mg/mL, ethanol/acetone/THF/water 30/30/30/10 (V/V)), was also applied with a Hamilton syringe.

TABLE-US-00008 TABLE 8 Paclitaxel on the stents directly after coating and loss upon introduction into the application system Paclitaxel on Loss of paclitaxel upon the stents directly introduction into the after coating [μg] application system [μg] Mean ± Mean ± Sample Measurements SD Sample Measurements SD RF-G- 1462 1420 ± RF-G- 89 90 ± 20-1 36 20-2 38 RF-G- 1401 RF-G- 53 20-3 20-4 RF-G- 1397 RF-G- 128 20-5 20-6

Example 7

[0092] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation with a Measured Volume of the Coating Solution

[0093] Coating solution: ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. The paclitaxel concentration in the coating solution was 20 mg/mL. In addition, iopromide was added in a concentration of 2 mg/mL. Coating was carried out by rotation of the medical device (21 rpm) and using a Hamilton microsyringe with a volume of 75 μL/Stent (4.0×60 mm).

[0094] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent=188.5 mm.sup.2, by distributing the solution over the irregular surface of the stent.

[0095] A stent coated in this manner is shown in FIG. 4. The coating solution used was a RF-C-20-UV-2 solution (paclitaxel 20 mg/mL and iopromide (2 mg/mL), ethanol/acetone/water 40/40/20 (V/V)). Application to the stent was again carried out with a Hamilton syringe.

TABLE-US-00009 TABLE 9 Paclitaxel on the stents directly after coating and loss upon introduction into the application system, no increase of loss with iopromide Loss of paclitaxel Paclitaxel on upon introduction the stents directly into the after coating application system Sample [μg] Mean ± SD Sample [μg] Mean ± SD RF-C-20-UV- 1440 1437 ± 25 RF-C-20-UV-2- 94 80 ± 30 2-1 2 RF-C-20-UV- 1411 RF-C-20-UV-2- 100 2-3 4 RF-C-20-UV- 1460 RF-C-20-UV-2- 45 2-5 6

Example 8

[0096] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation with a Measured Volume of the Coating Solution

[0097] Coating solution: ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. The paclitaxel concentration in the coating solution was 20 mg/mL. In addition, dexpanthenol was added in a concentration of 2 mg/mL. Coating was carried out by rotation of the medical device (21 rpm) and using a Hamilton microsyringe with a volume of 75 μL/per stent (4.0×60 mm).

[0098] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent=188.5 mm.sup.2, by distributing the solution over the irregular surface of the stent.

[0099] FIG. 5 shows a stent coated with RF-C-20-DP-2 coating solution, see Table 10 (paclitaxel 20 mg/mL and dexpanthenol (2 mg/mL) in ethanol/acetone/water 40/40/20 (V/V)). Here again, application to the stent was carried out with a Hamilton syringe.

TABLE-US-00010 TABLE 10 Paclitaxel on the stents directly after coating and loss upon introduction into the application system, no increase of loss with dexpanthenol Loss of paclitaxel Paclitaxel on upon introduction the stents directly into the after coating application system Sample [μg] Mean ± SD Sample [μg] Mean ± SD RF-C-20-DP- 1462 1460 ± 78 RF-C-20-DP-2- 64 60 ± 11 2-1 2 RF-C-20-DP- 1536 RF-C-20-DP-2- 68 2-3 4 RF-C-20-DP- 1381 RF-C-20-DP-2- 48 2-5 6

Example 9

[0100] Coating of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation, with a Measured Volume of the Coating Solution

[0101] Coating solution: ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. The paclitaxel concentration in the coating solution was 20 mg/mL. In addition, urea was added in a concentration of 2 mg/mL. Coating was carried out by rotation of the medical device (21 rpm) and using a Hamilton microsyringe with a volume of 75 μL/per stent (4.0×60 mm).

[0102] 4.0×60 mm stents having protruding elements for application of the medicinal product were coated (cf. ReFlow US 2017/0196717), total surface area of a stent=188.5 mm.sup.2, by distributing the solution over the irregular surface of the stent.

[0103] The stent coating in the stent shown in FIG. 6 was obtained by means of a RF-C-20-UR-2 coating solution (paclitaxel 20 mg/mL and urea (2 mg/mL), ethanol/acetone/water 40/40/20 (V/V), applied by means of a Hamilton syringe.

TABLE-US-00011 TABLE 11 Paclitaxel on the stents directly after coating and loss upon introduction into the application system, no increase of loss with urea Loss of paclitaxel Paclitaxel on upon introduction the stents directly into the after coating application system Sample [μg] Mean ± SD Sample [μg] Mean ± SD RF-C-20-UR- 1392 1432 ± 37 RF-C-20-UR- 47 66 ± 38 2-1 2-2 RF-C-20-UR- 1438 RF-C-20-UR- 109 2-3 2-4 RF-C-20-UR- 1466 RF-C-20-UR- 41 2-5 2-6

Example 10

[0104] Coating of Stents and Subsequent Fitting onto Uncoated Balloon Catheters

[0105] Stents having protruding elements for application of the medicinal product (cf. ReFlow US 2017/0196717) were provided with a coating which upon implantation guaranteed an immediate, substantially complete delivery of medicinal product. The coating solution contained 20 mg/mL paclitaxel or 20 mg/mL paclitaxel and 2 mg/mL dexpanthenol. The solvent mixture used was ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. Coating was carried out with rotation (21 rpm) using a Hamilton microsyringe with a volume of 75 μL/stent.

[0106] Balloon catheters with balloons of an appropriate size (balloon diameter=stent diameter, balloon length=stent length) were introduced into the application catheter for the stent from the proximal end, so that distally, the balloon protruded completely out of the application catheter. After coating, the stents were pushed over a folded balloon of the balloon catheter and subsequently adhered to the shaft of the balloon catheter, so that the balloon was located in the lumen of the coated stent. By pulling the balloon shaft lying in the application catheter through a metal block with tapered holes, the balloon and stent were compressed to the diameter of the application catheter and introduced into the latter.

Example 11

[0107] Coating of (a) Balloons of Balloon Catheters and (b) Stents with Subsequent Fitting of Coated Stent onto the Coated Balloon Catheter

[0108] Folded balloons (4.0×80 mm) of balloon catheters were inflated and coated under rotation (21 rpm). The coating solution contained 20 mg/mL paclitaxel or 20 mg/mL paclitaxel and 2 mg/mL dexpanthenol. The solvent mixture used was ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. The coating was carried out with a volume of 75 μL using a Hamilton syringe. The coated balloons were deflated and re-folded under vacuum by pushing on a PTFE tube.

[0109] Balloon catheters with coated folded balloons were introduced into the application catheter for the stent from the proximal end, so that distally, the balloon protruded completely out of the application catheter.

[0110] Stents having protruding elements for application of the medicinal product (cf. ReFlow US 2017/0196717) were provided with a coating which, upon implantation, guaranteed an immediate, substantially complete delivery of medicinal product. The coating solution contained 20 mg/mL paclitaxel or 20 mg/mL paclitaxel and 2 mg/mL dexpanthenol. The solvent mixture used was ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. Coating was carried out with rotation (21 rpm) using a Hamilton microsyringe with a volume of 75 μL/stent.

[0111] After coating, the stents were pushed the re-folded balloon of the balloon catheter described above and then adhered to the shaft of the balloon catheter so that the balloon was located in the lumen of the coated stent.

[0112] By pulling the balloon shaft lying in the application catheter through a metal block with tapered holes, the balloon and stent were compressed to the diameter of the application catheter and introduced into the latter.

Example 12

[0113] Coating of Stents with a Balloon of a Balloon Catheter in the Stent Lumen

[0114] The initially uncoated stents with the similarly uncoated balloons of the balloon catheter were in an application catheter. The distal end of the balloon catheter protruded from the application catheter with the balloon and stent. The stents with the protruding elements for medicinal products application, which were fastened to the shaft of a balloon catheter and for which the balloon was located in the lumen of the stent, were provided with a coating which guaranteed an immediate substantially complete delivery of medicinal product upon implantation.

[0115] The coating solution contained 20 mg/mL paclitaxel or 20 mg/mL paclitaxel and 2 mg/mL dexpanthenol. The solvent mixture used was ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. Coating was carried out with rotation (21 rpm) with a volume of 75 μL/per stent (4.0×60 mm) using a Hamilton microsyringe.

[0116] After drying, the balloon and stent were compressed to the diameter of the application catheter by pulling the balloon shaft lying in the application catheter through a metal block with tapered holes and introduced into the application catheter.

Example 13

[0117] Coating of Balloons of Balloon Catheters and Fitting in the Lumen of Uncoated Stents

[0118] Balloon catheters with folded balloons of an appropriate size (balloon diameter=stent diameter, balloon length=stent length+20 mm) were introduced into the application catheter for the stent from the proximal end, so that distally, the balloon protruded completely out of the application catheter.

[0119] The balloons (4.0×80 mm) were inflated and coated under rotation (21 rpm). The coating solution contained 20 mg/mL paclitaxel or 20 mg/mL paclitaxel and 2 mg/mL dexpanthenol. The solvent mixture used was ethanol/acetone/water, wherein the proportions of ethanol and acetone were respectively 40% by volume and the proportion of water corresponded to 20% by volume. Coating was carried out with a volume of 75 μL using a Hamilton microsyringe. The coated balloons were deflated after drying and re-folded under vacuum by pushing on a PTFE tube. The PTFE tubes were later removed.

[0120] Uncoated stents having protruding elements for application of the medicinal product (cf. ReFlow US 2017/0196717) were pushed over the coated balloons and adhered to the shaft of the balloon catheter in a manner such that the balloon was located in the lumen of the uncoated stent.

[0121] The balloon and stent were compressed to the diameter of the application catheter by pulling the balloon shaft in the application catheter through a metal block with tapered holes and introduced into the application catheter.

Example 14

[0122] Application Test of Stents with Immediate Substantially Complete Delivery of Medicinal Product Upon Implantation into Pigs

[0123] Following sterilization, stents from Examples 4, 5a, 7 and 8 were introduced into the iliaca intema, arteria femoralis and arteria profunda femoris of pigs (approx. 30 kg body weight) and deployed from the application catheter, then completely expanded for 2 min with an uncoated balloon catheter and then completely removed through a special retrieval mechanism without injuring the animal. Approximately 15 min after removal of the stent, in the case of using the stent of Example 4, 4.2±4.0% of the paclitaxel dose, of Example 5a, 5.1±2.4% of the dose, of Example 7, 4.0±0.6% of the dose and of Example 8, 9.9±7.0% of the dose was found in the arterial wall. These values were similar to the values measured after using clinically proven coated balloons (Scheller B, Speck U, Abramjuk C, Bermhardt U, Böhm M, Nickenig G. Paclitaxel balloon coating—a novel method for prevention and therapy of restenosis. Circulation 2004; 110: 810-814; Kelsch B, Scheller B, Biedermann M, Clever Y P, Schaiffner S; Mahnkopf D; Speck U, Cremers B. Dose-response to paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model. Invest Radiol 2011; 46:255-263). On average, 20% of the dose remained on the stents.

Example 15

[0124] Coating of Self-Expanding Nitinol Stents for Peripheral Arteries (VascuFlex®) Peripheral Stent, B. Braun Vascular Systems) 8×60 mm, Approx. 700 mm=Surface Area, Coated Using a Hamilton Microsyringe, Coating Solution: Ethanol/Acetone/Water 40140/20 V/V/V, 30 mg Paclitaxel/mL

TABLE-US-00012 TABLE 12 Paclitaxel on the stents directly after coating; loss upon introduction into the application system, reproducible coating of stents with a nitinol main body with resveratrol-containing coating solution. Formulation N O P Q Composition 25 mg/ 50 mg/ 50 mg/ 25 mg/ mL PTX, mL PTX, mL PTX, mL PTX, 7.5 mg/mL 15 mg/mL 15 mg/mL 7.5 mg/mL resveratrol resveratrol resveratrol resveratrol acetone/ THF/H.sub.2O acetone/ acetone/ THF/H.sub.2O (80/20) THF/H.sub.2O THF/H.sub.2O (50/36/14) (38/32/30) (46/96/15) Coating 84 42 42 84 volume [μL] Content after 1919 ± 53 1966 ± 26 1677 ± 105 2048 ± 31 coating, in μg/Stent