PHARMACEUTICAL COMPOSITIONS AND DEVICE METHODS FOR TREATMENT OF PROLIFERATIVE DISEASES

Abstract

A method for treating proliferative diseases by delivering a combination of at least two pharmaceutically active agents to a diseased area or tissue comprising a coating layer of two hydrophobic drugs applied to an exterior surface of a device or a substrate wherein the first pharmaceutically active agent is selected from a group consisting of mTor inhibitors and the second pharmaceutically active agent is selected from a group of consisting of NF-kβ inhibitors. Further a method for treating proliferative diseases by delivering a combination of at least two pharmaceutically active agents to a diseased area or tissue comprising: a coating layer of two hydrophobic drugs applied to an exterior surface of a medical device or substrate and a polymer blend carrier for the pharmaceutically active agents.

Claims

1. A method for treating proliferative diseases by delivering a combination of at least two pharmaceutically active agents to a diseased area or tissue comprising: a coating layer of two hydrophobic drugs; applied to an exterior surface of a device or a substrate; wherein the first pharmaceutically active agent is selected from a group consisting of mTor inhibitors and the second pharmaceutically active agent is selected from a group of consisting of NF-kβ inhibitors.

2. The method of claim 1, wherein the mTor inhibitor is rapamycin and the NF-kβ inhibitor is curcumin.

3. The method of claim 1, wherein the mTor inhibitor is rapamycin and the NF-kβ inhibitor is selected from a group consisting of: sulfasalazine, sulindac, indomethacin, diclofenal, etodolac, meclofenate, mefenamic acid, nambunetone, piroxicam, phenylbutazone, meloxicam, dexamethasone, betamethasone dipropionate, diflorsasone diacetate, clobetasol propionate, halobetasol propionate, amcinomide, beclomethasone dipropionate, fluocinomide, betamethasone valerate, triamcinolone acetonide, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, minocycline, cyclophosphamide, methotrexate, cyclosporine, leflunomide, etanercept, infliximab, ascomycin, β-estradiol, rosiglitazone, troglitazone, pioglitazone, S-nitrosoglutathione, gliotoxin G, panepoxydone, and cycloepoxydon tepoxalin and combinations thereof.

4. The method of claim 1, wherein the ratio by weight of the mTor inhibitor to the NF-kβ inhibitor in the coating layer is from 1:1 to 100:1.

5. The method of claim 1, wherein the combined initial drug loading is from 0.1 micrograms to 10 micrograms of pharmaceutically active agents per square millimeter of the device or substrate.

6. The method of claim 3, wherein the NF-kβ inhibitor is selected from a group consisting of: sulfasalazine, indomethacin, minocycline, rifampin and a combination thereof.

7. A method for treating proliferative diseases by delivering a combination of at least two pharmaceutically active therapeutic agents to a diseased area or tissue comprising: a coating layer applied to an exterior surface of two hydrophobic drugs on the exterior surface of a device or substrate, containing; a permeation enhancer; a combination of at least two pharmaceutically active therapeutic agents; wherein the first pharmaceutically active therapeutic agent is selected from a group consisting of mTor inhibitors and the second pharmaceutically active therapeutic agent is selected from a group of consisting of NF-kβ inhibitors.

8. The method of claim 7, wherein the permeation enhancer is citric acid.

9. The method of claim 7, wherein the permeation enhancer is dodecyl methyl sulfoxide (DMSO).

10. The method of claim 7, wherein the permeation enhancer is L-arginine.

11. The method of claim 7, wherein the permeation enhancer is sodium nitroprusside.

12. The method of claim 7, wherein the permeation enhancer is a nitric oxide (NO) donor.

13. The method of claim 7, wherein the permeation enhancer is selected from a group of S-nitrosothiols consisting of S-nitroso-N-acetylamine (SNAP), S-nitrosoglutathione (SNOGLU) and S-nitroso-N-valerylpenicillamine (SNVP) and a group of Diazeniumdiolates (NONOates) consisting of Diethyamino NONOate (DEA-NO), PROLI/NO, SPER/NO and V-PYRRO/NO.

14. A method for treating proliferative diseases by delivering a combination of at least two pharmaceutically active agents to a diseased area or tissue comprising: a coating layer of two hydrophobic drugs applied to an exterior surface of a medical device or substrate; a polymer blend carrier for the pharmaceutically active agents; wherein a first pharmaceutically active agent is selected from a group consisting of mTor inhibitors and a second pharmaceutically active agent is selected from a group consisting of NF-kβ inhibitors.

15. The method of claim 14, wherein the polymer blend carrier is a mixture of hydrophilic polyurethane and a polyacrylic polymer.

16. The method of claim 14, wherein the weight ratio of the polyurethane polymer to the polyacrylic polymer in the polymer blend carrier is from 1:1 to 10:1.

17. The method of claim 14, wherein the weight percentage of pharmaceutically active agents to the total weight of the polymer blend carrier is from 30% to 70%.

18. The method of claim 14, wherein the mTor inhibitor is rapamycin and the NF-kβ inhibitor is curcumin.

19. The method of claim 14, wherein the mTor inhibitor is rapamycin and the NF-kβ inhibitor is selected from a group consisting of: sulfasalazine, sulindac, indomethacin, diclofenal, etodolac, meclofenate, mefenamic acid, nambunetone, piroxicam, phenylbutazone, meloxicam, dexamethasone, betamethasone dipropionate, diflorsasone diacetate, clobetasol propionate, halobetasol propionate, amcinomide, beclomethasone dipropionate, fluocinomide, betamethasone valerate, triamcinolone acetonide, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, minocycline, cyclophosphamide, methotrexate, cyclosporine, leflunomide, etanercept, infliximab, ascomycin, β-estradiol, rosiglitazone, troglitazone, pioglitazone, S-nitrosoglutathione, gliotoxin G, panepoxydone, and cycloepoxydon tepoxalin and mixtures thereof.

20. The method of claim 14, wherein the ratio by weight of the mTor inhibitor in the coating layer to the NF-kβ inhibitor is from 1:1 to 100:1.

21. The method of claim 14, wherein the combined initial drug loading is from 0.1 micrograms to 10 micrograms of therapeutic agents per square millimeter of the device or substrate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] FIG. 1 shows an example of a drug-coated balloon of a balloon catheter according to the present invention.

[0064] FIG. 2 and FIG. 3 are examples of drug release from coated coupons into an aorta segment according to the formulations of the present invention.

[0065] FIG. 4 shows an example of a drug-coated balloon being inflated inside an aorta segment to allow drug transfer into the wall of the aorta.

[0066] FIG. 5 shows an example of drug transfer into the aorta wall after the balloon was inflated for 2 minutes to contact the aorta wall and the aorta was opened to expose the inside surface of the aorta.

[0067] FIG. 6 shows a graphical representation of a quantitative release of micrograms of a mixture of the pharmaceutical agents rapamycin and curcumin versus time according to an embodiment of the present disclosure.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0068] The pharmaceutical compositions described in this invention can be used to coat any surface of medical devices including plastics, metals, ceramic, and biological tissues and parts. As shown in FIG. 1, the medical device is a balloon. The balloon 10 is usually fabricated from plastic materials such as polyethylene, polypropylene, nylon, ethylene vinyl acetate and polyethylene terephthalate (PET). The coating formulation 20 consists of the first drug 30 and the second drug 40 in a proportional ratio. The first drug 30 is an mTor inhibitor and the second drug 40 is an NF-kβ inhibitor. The first drug 30 is rapamycin and the second drug 40 is curcumin. The ratio of rapamycin to curcumin is 3:1.

[0069] As shown in FIG. 2 and FIG. 3, the coating formulation 20 is coated on a piece of aluminum coupon 60. The coupon is then placed onto the inner surface of an opened aorta 50 with the drug surface in contact with inner surface of the aorta 50. After a few minutes, the coupon 60 is removed showing the area 70 of the aorta where the combination of drug 30 and drug 40 being transferred to the tissue of the aorta 50.

[0070] As shown in FIG. 4 and FIG. 5, a balloon 10 with a formulation coating 20 of this invention is being inflated inside an aorta 80 for a maximum time of two minutes. The aorta 80 is then cut opened exposing the surface 90 and showing the transferred of drug 30 and drug 40 into the inner layer of the aorta 80. The drug 30 is an mTor inhibitor and the drug 40 is an NF-kβ inhibitor. In this example, the mTor inhibitor is rapamycin and the NF-kβ inhibitor is curcumin. The ratio of rapamycin to curcumin is 3 to 1. It is advisable that any combination of an mTor inhibitor and an NF-kβ inhibitor can be used and with any ratio depending on the application of each proliferative disease.

[0071] FIG. 6 is a graphical representation of the cumulative releases, in micrograms, of individual NF-kβ inhibitor curcumin and mTor inhibitor rapamycin (first and second curve from the time axis. The third curve from the time axis is the combine total release of both drugs rapamycin and curcumin in micrograms. As shown in FIG. 6 the ratio of rapamycin release is roughly three times the rate of the release of curcumin as verified by the drug ratio of 3 to 1 in the formulation of the coating applied to a device embodiment of the present disclosure.

[0072] Embodiments of the present invention relate to medical devices, including particularly balloon catheters and stents, having a rapid drug-releasing coating and methods for preparing such coated devices. The therapeutic agent according to embodiments of the present invention does not require a delayed or long term release and instead is released in a very short time period, from seconds to minutes, to provide a therapeutic effect upon contact with tissue. An object of embodiments of the present invention is to facilitate rapid and efficient uptake of drug by target tissue during transitory device deployment at a target site.

[0073] In embodiments of the present invention, dipping and roller coating are the preferred methods because these processes allow one to control the uniformity of the thickness of the coating layer as well as the concentration of the therapeutic agent applied to the medical device. In addition, the operation is safer and less wasteful of materials, especially the pharmaceutical agents. Spraying might also be used but requires the use of more sophisticated equipment such as ultrasonic sprayers and isolators for potent compounds.

[0074] In embodiments of this invention, a single coating or multiple coatings can be applied to the intended medical device depending on the concentration of the total drugs in the formulation. The thickness of each coating might vary from about 0.1 microns to 100 microns in thickness depending on the number of dippings or drug concentrations in the formulation.

[0075] The following examples include embodiments of medical devices and coating layers within the scope of the present invention. While the following examples are considered to embody the present invention, the examples should not be interpreted as limitations upon the present invention.

[0076] Example Preparations of Coating Solutions Include the Following:

[0077] Formulation 1: 92.5 mg of rapamycin and 37.3 mg of curcumin in 6.5 ml of the organic solvent tetrahydrofuran (THF). The ratio of rapamycin to curcumin is about 3 to 1 by weight.

[0078] Formulation 2: 105.4 mg of rapamycin, and 108.7 mg of curcumin in 7.0 ml tetrahydrofuran (THF). The ratio of rapamycin to curcumin is about 1 to 1 by weight.

[0079] Formulation 3: 31.05 mg of rapamycin, 10.35 mg of curcumin and 3.60 mg of citric acid in 6.0 ml tetrahydrofuran (THF). The ratio of rapamycin to curcumin is about 3 to 1 by weight.

[0080] Formulation 4: 31.05 mg of rapamycin, 10.35 mg of curcumin and 3.82 mg of Dodecyl methyl sulfoxide (DMSO) in 6.0 ml tetrahydrofuran (THF). The ratio of rapamycin to curcumin is about 3 to 1 by weight.

[0081] Formulation 5: 45 mg of polymers (50% polyurethane, 50% polyacrylic acid), 31.05 mg rapamycin, 10.35 mg curcumin in 6.0 ml THF. The ratio of rapamycin to curcumin is 3 to 1.