MEDICAL PRODUCT FOR DELIVERY OF A DRUG WITH AN INTENSIFIED EFFECT

Abstract

The invention concerns a medical device for at least periodical contact with diseased vessels such as a stent or a balloon catheter, for example, as well as a method for coating it with a defined solution.

In accordance with the invention, a restenosis inhibitor is disposed on an outer surface in an active substance concentration of more than 4 μg/mm.sup.2.

Claims

1. A medical device for at least periodical contact with diseased vessels, comprising an elongated hollow body with an outer surface, wherein an active substance or active substance mixture comprising a restenosis inhibitor which is specific for delivery onto the vessel wall is disposed on the outer surface, characterized in that the active substance or the active substance mixture comprises or consists of paclitaxel as the restenosis inhibitor and is present on the surface, at least in regions, in a proportion of ≥6 μg/mm.sup.2, wherein the medical device is a balloon catheter, wherein furthermore, auxiliary substances are disposed on the outer surface, to be selected from a group consisting of organically bound iodine, urea, magnesium salts, dexpanthenol, iopamidol, iopromide, iomeprol, iohexol, magnesium stearate or combinations thereof.

2. (canceled)

3. (canceled)

4. The medical device as claimed in claim 1, wherein, in addition to the auxiliary substances, lipophilic antioxidants, in particular nordihydroguaiaretic acid, resveratrol and/or propyl gallate, are disposed on the outer.

5. The medical device as claimed in claim 1, characterized in that furthermore, an organically bound iodine is disposed on the outer surface at least in regions in a loading density in the range from 0.1 μg/mm.sup.2 to 0.5 μg/mm.sup.2.

6. The medical device as claimed in claim 1, characterized in that at least sections of the outer surface comprise a non-elastic, compression-resistant membrane, wherein the membrane is preferably constructed as a balloon of the device configured as a balloon catheter.

7. The medical device as claimed in claim 6, characterized in that, the membrane comprises or consists of polyamide, polyether block amide, polyethylene, polyethylene terephthalate or their copolymers and/or blends.

8. The medical device as claimed in claim 6, characterized in that the balloon can be inflated to more than 15 bar, in particular more than 30 bar.

9. A method for coating a medical device for the treatment of diseased vessels, comprising: coating the medical device with a solution comprising a solvent, a restenosis-inhibiting active substance and an auxiliary substance comprising organically bound iodine forming a matrix for the active substance, wherein the auxiliary substance contains the organically bound iodine in a concentration in the range from 1.2% to 12.5% by weight, preferably 2.5% by weight to 12.5% by weight with respect to the active substance in the solution, and wherein the organically bound iodine is present as iopromide, iopamidol and/or iomeprol.

10. (canceled)

11. The method as claimed in claim 9, characterized in that the solution contains paclitaxel in a concentration in the range from 100 mg to 200 mg in 5 mL of solution.

12. The method as claimed in claim 9, characterized in that the solution contains acetone, water and/or ethanol as the solvent, and wherein the solvent contains 3% to 25% by volume, in particular 5% to 15% by volume of water.

13. A method for coating a medical device for the treatment of diseased vessels, comprising the following steps in the given order: (a) preparing a solution comprising a solvent, a restenosis-inhibiting active substance and an auxiliary substance comprising organically bound iodine forming a matrix for the active substance, wherein the auxiliary substance contains the organically bound iodine in a concentration in the range from 1.2% to 12.5% by weight, preferably 2.5% by weight to 12.5% by weight with respect to the active substance in the solution, and wherein the organically bound iodine is present as iopromide, iopamidol and/or iomeprol; (b) applying the solution to at least regions of an outer surface of the device, preferably as claimed in claim 1, by means of dipping, spraying or wetting with a volumetric measuring device; and (c) drying the device.

14. The method as claimed in claim 13, characterized in that the device has an inflatable balloon and in step (b), an outer surface of the balloon is coated in the inflated state, at least in regions.

15. The medical device as claimed in claim 4, characterized in that furthermore, an organically bound iodine is disposed on the outer surface at least in regions in a loading density in the range from 0.1 μg/mm.sup.2 to 0.5 μg/mm.sup.2.

16. The medical device as claimed in claim 7, characterized in that the balloon can be inflated to more than 15 bar, in particular more than 30 bar.

17. The method as claimed in claim 11, characterized in that the solution contains acetone, water and/or ethanol as the solvent, and wherein the solvent contains 3% to 25% by volume, in particular 5% to 15% by volume of water.

Description

EXAMPLE 1

[0060] Increasing paclitaxel (Ptx) transfer from coated, EO-sterilised balloon into the treated arterial tissue (column 6) by changing the coating: reduction of auxiliary substance (column 4), increasing water content of coating solution (column 3) and coating balloon in expanded state (column 2). All balloons with approximately 3 μg paclitaxel/mm.sup.2 balloon surface. Methods: Experiments on coronary arteries from pigs; for method, see Scheller et al. 2004, Speck et al. 2018.

TABLE-US-00001 Column 3 4 7 2 Water Auxiliary 5 6 Ptx State of content of substance Paclitaxel Ptx remaining balloon coating (iopromide) on the transferred on used Group 1 during solution % by weight balloon into the arterial balloon no. Coating coating (v/v %)* of paclitaxel [μg] tissue % of (5) % of (5) A experimental inflated 1.3% 0 625 ± 111 16.0 ± 11.8 23.1 ± 10.2 B experimental inflated 1.4% 10 680 ± 326 19.1 ± 11.1 21.0 ± 14.7 C experimental inflated 10.0% 50 745 ± 31  29.9 ± 13.5 15.0 ± 10.0 D experimental inflated 1.3% 50 765 ± 66  25.9 ± 11.7 16.8 ± 4.7  paccocath coating Circ. paccocath folded 50 550 8.7 ± 4.9 7.9 ± 2.6 2004

[0061] By means of the balloon catheters coated in accordance with Example 7B of DE 10244847, on average 8.7% of the active substance paclitaxel was transferred into the arterial wall, the selected new coatings resulted in a significantly higher proportion of the dose in the vessel wall (19.1-29.9%), wherein the version without auxiliary substance (group A) remained unconsidered, because previous balloon coatings with paclitaxel without auxiliary substances had proved to be less effective in patients having regard to the desired inhibition of restenosis.

EXAMPLE 2

Increase of Dose on Balloon

[0062] Balloon catheters from Acotec, balloon dimensions 4×40 to 7×40 mm, were coated with paclitaxel using a composition with 10% by volume water and 10% by weight iopromide with respect to the active substance in the solution and inflated in the A. iliaca interna or A. femoralis of domestic pigs for 1 min (for method, see Scheller et al. 2004, Speck et al. 2018).

[0063] Column (1): paclitaxel (Ptx) in μg/mm.sup.2 of balloon surface, with respect to the balloon surface area, because the balloons have or may have different lengths for the treatment of different arteries and sections of arteries and (for applications other than those described here) a different diameter. Columns 2-4: paclitaxel in the treated arterial wall (segment of the A. iliaca interna or A. femoralis of domestic pigs, approximately 3 months old, approximately 25 kg in weight) 10-40 min after balloon deflation; column 5: proportion of original paclitaxel dose found on the balloon after removal from the animal (see column 1).

[0064] Line 4, column 1: number of measured balloon catheters; columns 2-4: number of arteries investigated; column 5: number of balloons used.

[0065] Line 5, columns 2-5: in each artery, a balloon coated with paclitaxel with a 3 μg/mm.sup.2 balloon surface was inflated for 1 min, then deflated and removed.

[0066] Line 6, columns 2-5: in each artery, two balloons coated with paclitaxel of the same type as in line 5 were inflated one after the other in the identical arterial segment in order to transfer more drug into the arterial wall.

[0067] Line 7: as in line 5, only one coated balloon was inflated in each arterial segment, but this had been coated with twice the quantity of paclitaxel.

TABLE-US-00002 Line Column no. 1 2 3 4 5 1 dose group Paclitaxel on Ptx transfer into Ptx transfer into Ptx transfer into Ptx remaining one balloon arterial wall arterial wall arterial wall on used balloon 2 total concentration in proportion of proportion of tissue dose dose 3 [μg/mm.sup.2] [μg] [μg/g] [% of column 1] [% of column 1] 4 n 8 8 8 8 5 standard 3.06 ± 0.09 379 ± 265 787 ± 738 15.5 ± 10.3 9.5 ± 2.4 dose 3 μg/mm.sup.2 6 2 balloons, 3.06 ± 0.09 694 ± 492 1287 ± 619  14.6 ± 10.9  9.8 ± 3.1* each with 3 μg/mm.sup.2 7 1 balloon, 5.88 ± 0.20 796 ± 564 1957 ± 1472 16.9 ± 11.5 5.5 ± 1.2 6 μg/mm.sup.2

[0068] Result and conclusion: With the dose of 3 μg/mm.sup.2 of balloon surface, the expected values for this type of coating in respect of the drug transfer into the tissue and finally the small amount remaining on the balloon were measured. The use of 2 identical catheters with inflation in exactly the same segment of the vessel resulted in almost double the quantity of drug in the artery. Doubling the dose on the balloon had at least the same effect. At least double the quantity of drug was transferred into the arterial wall. This should be understood to be an indication of increased efficacy.

EXAMPLE 3

Influence of Balloon Membrane and Composition of the Coating on the Transfer of Paclitaxel and Sirolimus onto the Arterial Wall in Pigs

[0069] Balloons of balloon catheters were coated as stated above with paclitaxel-containing (Ptx) or sirolimus-containing formulations in the expanded state, folded and sterilised with ethylene oxide; the loss of active substance was measured during passage through a haemostatic valve, a guide catheter filled with blood (length 1 m) and with a 1 minute dwell time in blood (line 5), lines 6-8 show results of the experiments on coronary arteries in pigs; for method see Example (1). PTCA=percutaneous transluminal coronary angioplasty, Pebax=polyether block amide, NDGA=nordihydroguaiaretic acid, BHT=butylhydroxytoluene.

TABLE-US-00003 PTCA balloon catheter (Kossel PTCA balloon catheter from MitrAssist Lifesciences Limited; Medtech, Suzhou City, China) Nylon/ No. Catheter Nylon/Pebax balloon membrane Pebax balloon membrane 1 Internal experiment IMTR 20180917 IMTR20181021, IMTR20190304 no. 2 Balloon membrane Nylon PEBAX n PEBAX/ n Nylon PEBAX n 3 Formulation, active D10d; Ptx, NDGA D10d; Ptx, MA- PG2; Ptx, Sirolimus, BHT substance, auxiliary NDGA propyl gallate substance 4 Total active 1.98 1.98 2 3.09 ± 0.09 4 4.8 ± 0.5 4.8 ± 0.3 3 substance on balloon, μg/mm.sup.2 5 Active substance 10.3 ± 6.5 4.4 ± 5.4 4 16.8 ± 2.6  3 3.7 ± 4.0 0.7 ± 2.2 3 loss in haemostatic valve, % of dose (line 4) 6 Transfer into pig  6.0 ± 3.4 26.2 ± 8.0  6 35.4 ± 8.0  9  19.0 ± 7.923 23.6 ± 12.9 6 arterial wall, coronary, % of dose (line 4) 7 μg/g of arterial 116 ± 55 497 ± 191 6 834 ± 305 9 673 ± 339 815 ± 467 6 tissue 8 Remainder on 30.1 ± 6.5 26.0 ± 2.5  6 4.2 ± 0.5 9 16.6 ± 4.8  16.5 ± 4.7  6 balloon, % of dose (line 4)

[0070] Results and conclusions: The balloons consisted of nylon or Pebax, and were indistinguishably transparent and smooth. A substantially homogeneous coating of the balloon membranes was obtained in the range from approximately 2 to 5 μg/mm.sup.2. On average over all experiments, approximately 10% of the dose was lost on passage through a haemostatic valve, a guide catheter filled with blood and the dwell time in the blood. The transfer of paclitaxel from formulations with the antioxidants NDGA and propyl gallate was unusually high at approximately 30% of the dose for the balloons with pebax membranes, both in a direct comparison with balloons produced from nylon membranes (6.0±3.4%) and also in comparison with data from the literature (Scheller et al., 2004: 7.9±2.6%, Speck et al. 2018: 7.8±3.4%). This led to high paclitaxel concentrations in the tissue (line 8). The substantially improved transfer of the active substance paclitaxel into the arterial tissue observed (in the combination of antioxidant and pebax balloon) is surprising and is an indication of intensified efficacy of this balloon catheter. The proportion of the dose which remained on the balloon (line 9) was not very different between pebax and nylon balloons, but much smaller when propyl gallate was used as the antioxidant.

EXAMPLE 4

Composition of a Coating in Accordance with WO 2004/028582 A1, Example 7, Optimized

[0071] 81.1% by volume of acetone, 8.8% by volume of ethanol, 0.4% by volume of Ultravist 370, 9.7% by volume of water, 150 mg of paclitaxel on 5 mL of coating solution.