Medical device for dispersing medicaments

Abstract

For selective treatment of diseased tissue sections or organ parts, the surface of medical devices entering into contact with areas thereof under pressure is coated with lipophilic substantially water-insoluble medicaments binding to various tissue components with good adherence thereto, said medicaments having an effect thereupon a short time after entering into contact therewith without exerting a harmful influence upon adjacent healthy tissue.

Claims

1. A medical device comprising a balloon having a balloon surface comprising paclitaxel and a biocompatible organic or inorganic salt on the balloon surface; wherein the paclitaxel and the biocompatible organic or inorganic salt are present as a dry solid on the balloon surface without an inert matrix comprising a polymer, hydrogel, or microcapsule.

2. The medical device of claim 1 wherein said medical device further comprises a stent.

3. The medical device of claim 1 wherein the balloon surface has preformed longitudinal folds maintaining an inclination to refold after inflation.

4. The medical device of claim 3 wherein at least an area covered by the folds is covered with the paclitaxel and the biocompatible organic or inorganic salt.

5. The medical device of claim 3 wherein only an area covered by the folds is covered with the paclitaxel and the biocompatible organic or inorganic salt.

6. The medical device of claim 1 wherein the balloon surface consists of a material to which the paclitaxel and the biocompatible organic or inorganic salt adhere sufficiently well to resist forces required for folding, essentially without damage.

7. The medical device of claim 1 wherein the paclitaxel comprises amorphous structures with particle sizes of less than 5 microns.

8. The medical device of claim 1 wherein the concentration of paclitaxel on said surface is up to 5 g/mm.sup.2.

9. The medical device of claim 1 wherein the biocompatible organic or inorganic salt comprises a benzoate.

10. The medical device of claim 1 wherein the biocompatible organic or inorganic salt comprises a salicylic acid salt.

Description

EXAMPLE 1

(1) Coating an Expanded Balloon Catheter with Paclitaxel in Ethyl Acetate

(2) Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, product name Joker Lite, balloon dimensions 2.5 mm by 20 mm, are inflated to the maximum and immersed full length for 1 minute in ethyl acetate, 18.8 mg Paclitaxel per ml, +1% pharmaceutical olive oil, dried: Paclitaxel content 39 micrograms (after extraction with ethanol, HPLC).

EXAMPLE 2

(3) Coating a Folded Balloon Catheter with Paclitaxel in Ethyl Acetate

(4) Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, product name Joker Lite, balloon dimensions 2.5 mm by 20 mm, are immersed full length in folded condition for 1 minute in ethyl acetate, 18.8 mg Paclitaxel per ml, +1% pharmaceutical olive oil, and dried:

(5) Paclitaxel content 69 micrograms.

EXAMPLE 3

(6) Coating a Folded Balloon Catheter with Paclitaxel in Ethyl Acetate

(7) a) Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, product name Joker Lite, balloon dimensions 2.5 mm by 20 mm, are immersed full length in folded condition for 1 minute in ethyl acetate, 16.6 mg Paclitaxel per ml, and dried for 4 hours: Paclitaxel content 54 micrograms. b) Same procedure, but additional two times immersed for 5 seconds with 1 hour drying time after each immersion process in solution A (=3.33 ml ethyl acetate+100.0 mg of Paclitaxel): Paclitaxel content 126 micrograms. c) Same procedure, but additional four times immersed for 5 seconds with 1 hour drying time after each immersion process in the same solution: Paclitaxel content 150 micrograms.

EXAMPLE 4

(8) Coating a Balloon Catheter with Paclitaxel in Acetone

(9) Dissolve 350 mg of Paclitaxel in 9.0 ml of acetone; balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, product name Joker Lite, balloon dimensions 2.5 mm by 20 mm, are inflated to the maximum and immersed full length for 1 minute and removed. The solvent is dried for 12 hours at room temperature. Then the balloon is deflated and folded in the common way using a PTFE-coated tool. Optionally, one can crimp a stent of suitable dimensions onto the balloon: 29 micrograms of Paclitaxel on the balloon.

EXAMPLE 5

(10) Coating a Balloon Catheter with Paclitaxel in Acetone

(11) a) Immersion of folded balloon catheters made by BMT, product name Allegro, balloon dimensions 2.5 by 20 mm in a mixture of 0.15 ml ethanol+4.5 l of Ultravist 300 (an X-ray contrast agent made by Schering AG, Berlin, Germany)+1.35 ml of acetone+0.8 mg of Sudan red+30.0 mg of Paclitaxel: The folded balloon sections of the catheters are immersed 5 times, the first time for one minute, then dried for 3 hours, then 4 times at 1 hour intervals for 5 seconds each; subsequently, a stent was crimped on and the catheter was sterilized in the common way using ethylene oxide: Paclitaxel content 172 micrograms, no decomposition products of the active agent were determined using HPLC b) A saturated aqueous mannitol solution is used instead of Ultravist 300 c) A saturated aqueous sodium salicylate solution (pH 7.5) is used instead of Ultravist 300 d) 5 mg of acetylsalicylic acid are added to the completed solution according to (5a). e) 5 mg of glycerin are added to the completed solution according to (5a).

EXAMPLE 6

(12) Adhesion of the Active Agent in the Bloodstream

(13) 12 balloon catheters made by BMT, product name Allegro, balloon dimensions 2.5 by 20 mm, were used. The folded balloon sections of 6 catheters each were either 5 times immersed in [0.15 ml of ethanol+4.5 l of Ultravist 300+1.35 ml of acetone+0.8 mg of Sudan red+30.0 mg Paclitaxel] or 5 times in [1.5 ml of ethyl acetate+0.8 mg Sudan red+31.0 mg Paclitaxel], the first time for 1 minute each with 35 hours of drying time, then 4 times for 5 seconds each at 1 hour intervals; then 3 of the folded balloons of each group were gently moved for 5 minutes at 37 C. in 50 ml of human blood and removed to determine the Paclitaxel content: Reduction of mean values (n=3 per coating method) by 5 minutes of movement in blood as compared to 3 control catheters that were not incubated in blood. Acetone: 12% Ethyl acetate: 10%

EXAMPLE 7

(14) Examination of Restenosis Inhibition after Angioplasty and Stent Implantation in Coronary Arteries of Pigs

(15) Folded balloon catheters of the Joker Lite type made by BMT, 3.5 by 20 mm or 3.0 by 20 mm were immersed for 1 minute either in solution A) 3.33 ml of ethyl acetate (EA)+100.0 mg of Paclitaxel, or in solution B) 0.45 ml of ethanol+100 l of Ultravist-370+4.5 ml acetone (ac)+150.0 mg Paclitaxel and dried over night at room temperature. One more (low dose=L) or 4 more (high dose=H) immersion process(es), respectively, were carried out for just five seconds at 1 hour intervals on the next day.

(16) Active agent content after 2 immersions in solution (B) averaged 250 g, after 5 immersions in solution (B) 500 g, in solution (A) 400 g.

(17) The catheters coated with Paclitaxel or uncoated were used to implant stents into the left anterior or lateral coronary artery of a total of 22 pigs, and the vessels were slightly overdilated to stimulate restenosis by tissue hyperplasia. The animals were reangiographed after 5 weeks, and the vessel stenosis shown in the angiograms was measured using an automatic computer program.

(18) TABLE-US-00001 Group Stenosis (%) Uncoated 50.49 AcL 20.22 EAH 36.01 AcH 0.86 P .004

(19) Quantitative coronary angiography 5 weeks after stent implantation with uncoated and coated catheters; stenosis=reduction of lumen diameter in percent in the area of the stent as compared to the lumen diameter immediately after stent implantation; mean value and statistical significance of the effect of treatment.

EXAMPLE 8

(20) Active Agent Content of the Catheters after Vessel Dilatation and Stent Implantation

(21) After stent implantation and removal from the animals, the balloons from Example 8 ca. 3 cm in length were cut off the balloon catheters and placed in 1.5 ml of ethanol. Paclitaxel content was determined using HPLC. All available coated balloons and a selection of uncoated balloons were examined.

(22) Coronary,

(23) TABLE-US-00002 3.0 by 20 mm, coating: Ac high 38 4 g (n = 4) Ac low 22 5 g (n = 2) EEE high 41 (n = 1) 3.5 by 20 mm, coating: Ac high 37 10 g (n = 8) Ac low 26 6 g (n = 8) EEE high 53 9 g (n = 9) Uncoated (independent of size and vessel area) 0.9 1.0 g (n = 7)

(24) It follows from Example 6 that a maximum of 10% of the dose is lost before the balloon is inflated and about 10% of the dose remain on the balloon.

EXAMPLE 9

(25) Probucol is added to acetone at a concentration of 100 mg per ml; the solution is used to coat balloon catheters as described in the above examples.

EXAMPLE 10

(26) Rapamycin is dissolved at a concentration of 10 mg/ml in diethyl ether. The balloon sections of the catheters are coated as described in the above examples; after removal from the coating solution, the balloons should be brought into a horizontal position and continuously be turned around their longitudinal axis as soon as possible.

EXAMPLE 11

(27) Epothilone B is dissolved in ethyl acetate at a concentration of 2 mg/ml; the solution is used to coat balloon catheters as described in the above examples.