COATED BALLOON CATHETER AND COMPOSITION FOR COATING SAID BALLOON CATHETER

Abstract

The invention relates to a coated balloon catheter with a catheter substrate and a coating on the catheter substrate. The coating comprises a pharmaceutically active ingredient embedded in a binder matrix. The binder matrix consists of a polyethylene glycol-polyvinyl alcohol copolymer (PEG-PVA copolymer) and optionally shellac or a shellac derivative and additional pharmaceutically acceptable additives. A composition for coating the balloon catheter comprises the pharmaceutically active ingredient and a binder consisting of a PEG-PVA copolymer and optionally shellac or a shellac derivative. The active ingredient and the binder are dissolved in a solvent consisting of water, DMSO and at least one additional organic solvent indefinitely miscible with water.

Claims

1. A coated balloon catheter comprising a catheter substrate and a coating on the catheter substrate, the coating comprising a pharmaceutically active ingredient embedded in a binder matrix, wherein the binder matrix consists of a polyethylene glycol-polyvinyl alcohol copolymer (PEG-PVA copolymer) and optionally shellac or a shellac derivative.

2. The balloon catheter according to claim 1, wherein the active ingredient is selected from the group consisting of anti-proliferative, immunosuppressive, anti-inflammatory, anti-phlogistic, anti-hyperplastic, anti-neoplastic, anti-mitotic, cytostatic, cytotoxic, anti-angiogenic, anti-restenotic, microtubule inhibiting, anti-migrative and/or anti-thrombotic active ingredients, in particular cortisone, everolimus, biolimus, tacrolimus, paclitaxel and/or rapamycin.

3. The balloon catheter according to claim 1, wherein the PEG-PVA copo-lymer has a PEG content of 15 to 30 mole percent and a PVA content of 70 to 85 mole percent.

4. The balloon catheter according to claim 1, wherein the PEG-PVA copolymer has an average molar mass M.sub.n of 30,000 to 60,000 g/mole.

5. The balloon catheter according to claim 1, wherein the weight ratio of the active ingredient to the PEG-PVA copolymer in the coating is in a range of from about 10:1 to 1:2.

6. The balloon catheter according to claim 1, wherein the weight ratio of the active ingredient to the PEG-PVA copolymer in the coating is in a range of from about 2:1 to 1.1.

7. The balloon catheter according to claim 1, wherein the binder matrix contains shellac or a shellac derivative, and wherein the weight ratio of shellac or the shellac derivative to the PEG-PVA copolymer in the coating is less than or equal to 1:1.

8. The balloon catheter according to claim 1, wherein the loading of the catheter substrate with the active ingredient is in a range of from 0.5 μg/mm.sup.2 to 10 μg/mm.sup.2 relative to the outer surface of the substrate when expanded.

9. The balloon catheter according to claim 1, wherein weight of the coating applied onto the catheter substrate is in a range of from 0.75 μg/mm.sup.2 to 20 μg/mm.sup.2.

10. The balloon catheter according claim 1, wherein the active ingredient is in the form of active ingredient particles embedded in the binder matrix.

11. The balloon catheter according claim 1, wherein the active ingredient particles are present in the form of nanoscopic and/or microscopic particles.

12. A composition for coating of a balloon catheter, the composition comprising a pharmaceutically active ingredient and a binder dissolved in a solvent mixture, wherein the binder consists of a PEG-PVA copolymer and optionally shellac or a shellac derivative, and wherein the solvent mixture comprises water and at least one additional organic solvent fully miscible with water.

13. The composition according to claim 12, wherein the composition contains water in a percentage of 5 to 40 volume percent.

14. The composition according to claim 12, wherein the solvent mixture additionally contains DMSO in a percentage of up 10 volume percent, relative to the total volume of water and the additional organic solvent.

15. The composition according to claim 12, wherein the additional organic solvent comprises at least one of ethanol and methanol.

16. The composition according to claim 12, wherein the concentration of the active ingredient in the coating composition is up to 25 mg/ml.

17. The composition according to claim 12, wherein the solids content in the coating solution is up to 150 mg/ml.

18. The composition according to claim 12, consisting of the pharmaceutically active ingredient at a concentration of up to 25 mg/ml, wherein the pharmaceutically active ingredient is selected from the group consisting of an anti-proliferative compound, and immunosuppressive compound and mixtures thereof; the PEG-PVA copolymer at a concentration of 1 to 50 mg/ml, a water-soluble shellac derivative at a concentration of 0 to 50 mg/ml; water in an amount of 5 to 40 volume percent, at least one of methanol and ethanol in an amount of 60 to 94 volume percent; and DMSO in a percentage of 0 to 10 volume percent, preferably 0.5 to 10 volume percent.

19. A method for the production of a composition of claim 12, comprising the steps of: a) providing an aqueous solution of a PEG-PVA copolymer and optionally a water-soluble shellac derivative; b) gradually adding at least one additional organic solvent indefinitely miscible with water to the aqueous solution of step a) to form an aqueous-organic solution; c) mixing the aqueous-organic solution with a pharmaceutically active ingredient and homogenizing the mixture to form a coating solution containing the active ingredient; d) optionally adding DMSO in a percentage of up to 10 volume percent to the coating solution containing the active ingredient of step c) relative to the total volume of water and organic solvent.

20. A method for the production of a coated balloon catheter according to claim 1, comprising the steps of: a) providing an aqueous solution of a PEG-PVA copolymer and optionally a water-soluble shellac derivative; b) gradually adding at least one additional organic solvent indefinitely miscible with water to the aqueous solution of step a) to form an aqueous-organic solution; c) mixing the aqueous-organic solution with a pharmaceutically active ingredient and homogenizing the mixture to form a coating solution containing the active ingredient; d) optionally adding DMSO in a percentage of up to 10 volume percent to the coating solution containing the active ingredient of step c) relative to the total volume of water and organic solvent; and e) applying the coating solution containing the active ingredient of step c) or d) onto a surface of a balloon catheter and drying the coating solution to form a coated balloon catheter.

Description

DESCRIPTION OF THE DRAWING

[0064] FIG. 1 shows an electron microscopic image of a paclitaxel/PEG-PVA/shellac (2:1:0.5) coating in the composition magnified 500 times, obtained from a coating solution without DMSO; and

[0065] FIG. 2 shows an electron microscopic image of a paclitaxel/PEG-PVA/shellac coating magnified 500 times, having a PEG-PVA to paclitaxel ratio of 1:2, obtained from a coating solution additionally containing 3% DMSO.

PRODUCTION OF A COATING SOLUTION

Example 1

[0066] First, 25 mg of a PEG-PVA graft copolymer was dissolved in 2 ml water. The PEG content of the PEG-PVA graft polymer was 25 mole percent. A homogeneous polymer solution was formed by gradually adding 8 ml ethanol in fine doses. The anti-proliferative active ingredient paclitaxel was provided in an amount of 50 mg as a solid and added while exposed to ultrasound. Then, a percentage of 12.5 mg of an ammonium salt of shellac was added to the solution. A clear solution with a solid content of 8.75 mg/ml solvent and an ethanol:water volume ratio of 80:20 was obtained.

Example 2

[0067] As described in Example 1, 25 mg of a PEG-PVA graft copolymer was dissolved in 2 ml water. The PEG content of the PEG-PVA graft polymer was 25 mole percent. A homogeneous polymer solution was formed by gradually adding 8 ml ethanol in fine doses. The anti-proliferative active ingredient paclitaxel was provided in an amount of 50 mg as a solid and added while exposed to ultrasound. In addition, 0.3 ml DMSO was added to this solution. A clear solution with a solid content of 7.5 mg/ml solvent and an ethanol:water volume ratio of 80:20 and a DMSO content of additively 3% relative to the total volume of ethanol and water was obtained. Solution experiments showed that the water content of the coating solution can be increased to a maximum of 40 volume percent without paclitaxel precipitating from the solution.

Example 3

[0068] As described in Example 2, a solution of 25 mg of a PEG-PVA graft copolymer in 2 ml water was produced. The PEG content of the PEG-PVA graft polymer was 25 mole percent. A homogeneous polymer solution was formed by gradually adding 8 ml ethanol in fine doses. The anti-proliferative active ingredient paclitaxel was provided in an amount of 50 mg as a solid and added while exposed to ultrasound. A stable, clear solution with a solid content of 7.5 mg/ml solvent and an ethanol:water volume ratio of 80:20 was obtained. The solution did not contain DMSO.

[0069] Coating Experiments

[0070] A smooth-walled balloon of a commercially available balloon catheter was coated with a coating solution according to Example 1. The coating solution was applied onto the surface of the balloon catheter by spray coating.

[0071] Following the application of the coating solution the balloon's surface was dried by warm air at a temperature between 30 and 60° C. Drying left a tightly adhesive and mechanically stable coating substantially made of nanoscopic paclitaxel in the form of needle-like particles which were embedded in a binder matrix made of the PEG-PVA copolymer and shellac.

[0072] The electron microscopic image of FIG. 1 of a coating produced by using the coating solution of the invention pursuant to Example 1 shows that there is a coating present in the form of needle-like nanoscopic paclitaxel particles linked to each other like in a network.

[0073] Drying of the coating solution pursuant to Example 2, without addition of shellac but with a percentage of additively 3% DMSO, on the balloon's surface also resulted in a stable and tightly adhesive coating containing needle-like paclitaxel microparticles in a binder matrix made of PEG-PVA copolymer.

[0074] FIG. 2 shows an electron microscopic image of the coating obtained by using the coating solution pursuant to Example 2 and containing DMSO but no shellac. Microscopically, the coating has a needle-like structure and exhibits a distinct phase separation.

[0075] The coating solution pursuant to Example 3 resulted in a coating with a nanoscopic structure of the active ingredient particles, similar to the coating obtained by using the coating solution pursuant to Example 1.

[0076] Loading of the surface of the balloon catheter with paclitaxel can be freely set by using the method of the invention. Both the resistance of the coating and the structurization of the active ingredient can be further controlled by the ratio of the active ingredient to the water-soluble binder.

[0077] The balloon catheter thus produced is particularly suitable for treatment of residual stenosis after vascular dilatation or stent placement.