Uses for medical devices having a lubricious, nitric oxide-releasing coating

Abstract

Methods are provided for delivering nitric oxide to the vascular tissue of a patient to inhibit or prevent restenosis or improve vascular function following various surgical procedures or associated with various NO-related conditions. The disclosed methods comprise contacting the vascular tissue of a patient with a medical device coated with a coating comprising nitric oxide associated with and releaseable from a polyurea network formed from the reaction on said medical device of a polyisocyanate; an amine donor and / or hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.

Description

[0001] This application is a continuation-in-part of U.S. application Ser. No. 09 / 405,024, filed Sep. 27, 1999, which is a continuation-in-part of U.S. application Ser. No. 09 / 163,038, filed Sep. 29, 1998, which applications are herein incorporated by reference in their entirety.[0002] 1. Field of the Invention[0003] This invention relates generally to the uses for a drug-coating complex which is drug-releasing in physiological media. More particularly, the invention relates to methods of using medical devices coated with a lubricious, nitric oxide-releasing coating for the treatment of vascular disorders, including restenosis, and the induction of angiogenesis.[0004] 2. Related Art[0005] It has long been known that hydrophilic coatings with low friction (coefficient of friction of 0.3 or less) are useful for a variety of medical devices such as catheters, catheter introducers and the like. When low friction surfaces are used, the devices, upon introduction into the body, slide easi...

AI Technical Summary

Benefits of technology

[0046] According to the present invention, a lubricious coating is formed by the reaction, on a substrate to be coated, of a mixture comprising a polyisocyanate; an amine donor and / or a hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid; in a solvent. The resulting coating is drug-accommodating and, when the optional hydrophilic polymer is incorporated into the mixture, becomes highly lubricious.

[0079] Conventional pigments may be added to the coating mixture to impart color or radiopacity, or to improve the appearance of the coatings.

Problems solved by technology

However, in many cases the selection of materials does not provide the anti-slip properties desired in conjunction with other desirable properties for the particular medical device.

First, the exact ratio of primer material to the hydrophilic polymer is difficult to control, as it depends on whatever amounts of primer and hydrophilic polymer happen to be deposited by the wet film during the respective coating steps.

Second, the primer may begin to redissolve in the second coating solution, causing some loss of primer and further resulting in difficulty in controlling the primer / hydrophilic polymer ratio.

Third, the hydrophilic polymer is not covalently bonded to the substrate and may bond to other materials in the area leading the coating to lose its desired properties.

Fourth, additional facilities and time are needed for coating with a two step process, as compared to a one step process.

These coatings often lack good durability.

However, the multistep procedure makes it difficult to tailor the properties and values of the final coatings.

The coating formed, however, is not lubricious.

However, the one step coating process is only suitable for polymeric substrates.

Exposure to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions.

For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels.

Similarly, the implantation of urinary catheters can cause infections, particularly in the urinary tract.

Other adverse reactions to medical devices include inflammation and cell proliferation which can lead to hyperplasia, occlusion of blood vessels, platelet aggregation, rejection of artificial organs, and calcification.

Several hypotheses regarding the mechanism of action of NO in various processes have been put forward but none has yet been proven conclusively.

Because NO is such a potent, multifaceted biological response modifier, the challenge in the development of NO-based pharmaceuticals is to deliver an effective amount locally.

Restenosis limits the successful outcome of percutaneous procedures used to recanalize atherosclerotic coronary arteries.

The major problem associated with PTCA is the occurrence of restenosis (late arterial narrowing) which occurs in about 30-40 percent of all patients undergoing PTCA (Blackshear et al.

These procedures are more expensive, more traumatic, and therefore less preferred except in unusual circumstances.

However, its utility remains limited by the fact that (i) it is administered systemically and, unless heparin dose is carefully controlled, it can lead to bleeding complications; (ii) it is only effective in 20-30 percent of cases; and (iii) its high price has limited its widespread use for all angioplasty patients (Holmes, D. R. N. Engl. J. Med 336:1748-1749 (1997)).

Unfortunately, short therapeutic half-life, drug tolerance and systemic absorption with potentially adverse hemodynamic effects limit the use of conventional nitrate preparations.

Although exciting, such gene transfers are costly and relatively inefficient.

Because nitric oxide, in its pure form, is a highly reactive gas having limited solubility in aqueous media, it is difficult to introduce in a reliable and controllable form.

NO is too reactive to be used without some means of stabilizing the molecule until it reaches the treatment site.

Circ. Res. 78:337-342 (1996)) but would be difficult clinically.