WO2007053578A2 - Multi-phasic nitric oxide and drug co-eluting stent coatings - Google Patents

Multi-phasic nitric oxide and drug co-eluting stent coatings Download PDF

Info

Publication number
WO2007053578A2
WO2007053578A2 PCT/US2006/042376 US2006042376W WO2007053578A2 WO 2007053578 A2 WO2007053578 A2 WO 2007053578A2 US 2006042376 W US2006042376 W US 2006042376W WO 2007053578 A2 WO2007053578 A2 WO 2007053578A2
Authority
WO
WIPO (PCT)
Prior art keywords
release
nitric oxide
material
antiproliferative
polymer
Prior art date
Application number
PCT/US2006/042376
Other languages
French (fr)
Other versions
WO2007053578A3 (en
Inventor
Robert E. Raulli
Original Assignee
Amulet Pharmaceuticals, Inc.
Doletski, Blaine G.
Kalivretenos, Aristotle G.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US73141405P priority Critical
Priority to US60/731,414 priority
Priority to US74226405P priority
Priority to US60/742,264 priority
Application filed by Amulet Pharmaceuticals, Inc., Doletski, Blaine G., Kalivretenos, Aristotle G. filed Critical Amulet Pharmaceuticals, Inc.
Publication of WO2007053578A2 publication Critical patent/WO2007053578A2/en
Publication of WO2007053578A3 publication Critical patent/WO2007053578A3/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114Nitric oxide, i.e. NO
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Abstract

The present invention relates generally to nitric oxide (NO) and drug releasing polymers that may be applied to medical devices. More specifically, the present invention relates to compositions, materials, methods and devices whereby the release of nitric oxide and an additional biologically active agent from a vascular medical device may be temporally separated in order to achieve a therapeutic effect that is more beneficial than the release of either nitric oxide or the biologically active agent alone or simultaneous release of nitric oxide and the biologically active agent.

Description

MULTI-PHASIC NITRIC OXIDE AND DRUG CO-ELUTING

STENT COATINGS

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority from US Provisional Application 60/731,414, filed 10/31/2005, and US Provisional Patent Application 60/742,264, filed December 6,

2005, incorporated herein by reference in their entirety.

BACKGROUND

The present invention relates generally to nitric oxide (NO) and drug releasing polymers that may be applied to medical devices. More specifically, the present invention relates to compositions, materials, methods and devices whereby the release of nitric oxide and an additional biologically active agent from a vascular medical device may be temporally separated in order to achieve a therapeutic effect that is more beneficial than the release of either nitric oxide or the biologically active agent alone or simultaneous release of nitric oxide and the biologically active agent.

Stents and PES

Cardiovasular stents have been used clinically for treatment of occluded cardiac arteries for over fifteen years and their use has resulted in substantial clinical benefit for cardiac patients. A significant problem with bare-metal stents in clinical usage is restenosis of the artery, leading to recurrence of the primary cardiac symptoms and effects (LaI et al. 2003; Babapulle et al., 2004 and references therein).

The antirestenotic benefits of drug eluting stents (DES) have been documented and various products are commercially available (Columbo A and Iakovou, 2004; Hill et al., 2004, Babapulle et al., 2004). The known benefits of drugs typically found on DES are generally due to their antiproliferative properties. Thus, many of the typical drugs developed for DES work on the symptoms of restenosis but not on their underlying causes.

Benefits of nitric oxide in stented angioplasty The benefits of nitric oxide-eluting stents (NO ES) have also been well documented in animals (reviewed in Janero and Ewing, 2000). The benefits of NO ES include: 1) inhibition of fibrinogen-activated platelet adhesion resulting from fibrinogen binding to the stent biomaterial (Radomski et al., 1987; Venturini et al., 1992), 2) the restenosis-triggering subsequent release of platelet derived growth factors after platelet activation, 3) NO-stimulated acceleration of stent and surrounding tissue endothelialization (as supported by Morbidelli et al, 2003; Ziche et al., 1997), 4) direct inhibition of restenosis by inhibiting growth of smooth muscle cells (as supported by Mooradian et al., 1995), 5) direct inhibition of inflammation and related reduction of inflammatory growth factors (Dal Secco et al, 2003), and 6) inhibition of macro thromboses (Frost et al., 2002).

There is a need for better technology addressing the release of NO and additional drugs in drug eluting stents.

SUMMARY OF THE INVENTION

In one embodiment, the current invention is a material for coating medical devices that comprises: one or more layers coated on a medical device and capable of releasing NO and at least one antiproliferative agent, wherein the release of the NO and the agent are temporally separated. In another embodiment, the medical device is a cardiac stent. In a further embodiment, the NO is released by a NO donor. The NO donor may be a C-diazeniumdiolate. In another embodiment, the C-diazeniumdiolate is a modified polystyrene bead or a copolymer of modified vinylacetate or other acidic moiety. In another embodiment, the C-diazeniumdiolate polystyrene bead is embedded into a polymer. In another embodiment, the NO release substantially occurs during the period immediately following implantation of the medical device and the antiproliferative agent release substantially occurs during the period following the NO release.

In another embodiment, the NO is released within a period of from 1 minute to 48 hours, from 48 hours to 40 days, or from 1 hour to 48 days. In a further embodiment, the NO-releasing layer is selected from the group consisting of C-diazeniumdiolates, O-diazeniumdiolates, N-diazeniumdiolates, Nitrosothiols, organic nitrates and nitrites, nitroprusside and other iron nitrosyl compounds, ruthenium/NO or other metal/NO complexes, heterocyclic N-oxides, mesoionic heterocycles, C-nitroso compounds, oximes, N-hydroxyguanidines and N- hydroxyureas, and other nitric oxide releasing compound.

In another embodiment, the antiproliferative agent is selected from the group consisting of paclitaxel, sirolimus, everolimus, pimecrolimus, tacrolimus, zotarolimus, dexamethasone, 17β-estradiol, andNSAID's. In other aspects, the current invention is drawn to a device comprising: a cardiac stent that provides an initial release of NO for a therapeutically relevant period and a subsequent release of an antiproliferative drug for a second therapeutically relevant period. In another embodiment, the device comprises: a cardiac stent that provides an initial release of NO for a therapeutically relevant period following implantation and that substantially delays release of an antiproliferative drug for the same period.

In other aspects, the current invention is drawn to a method for coating a medical device comprising: coating the device with a first polymer layer containing an antiproliferative drug and a second polymer layer containing a NO-releasing agent. In another embodiment, the method for coating a medical device comprises: coating the stent with a first inner polymer layer containing at least one antiproliferative or anti-inflammatory drug, a second intermediate layer comprising a polymer capable of delaying the release of the antiproliferative drug from the inner layer, and a third outer layer containing a NO-releasing agent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the ability to provide short term bursts of NO from a polymethacrylate outer layer by doping in a short half-life NO donor.

Figure 2 demonstrates a release of plateau phase of NO using a long half-life donor drug (DET A/NO) in a polymethacrylate outer coating. The y axis measures pmoles/min/cm2 for each day tested. Figure 3 demonstrates the ability to release NO from an outer coating for at least 9 days using NO-releasing polystyrene beads embedded in a polymethacrylate polymer. The y axis measures pmoles/min/cm2 for each day tested.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Localized NO release appears to address some of the root causes of the restenotic lesion including: 1) the fibrinogen binding-platelet adhesion-release of platelet derived growth factor cycle and 2) inflammation and associated release of growth factors.

NO release also addresses associated problems with undesired smooth muscle cell growth (Mooradian et al., 1995), and provides a long-term biocompatible solution to the presence of the stent by stimulating rapid endothelialization of the stent itself. Stent endothelialization results in a natural cell coating for the stent that essentially makes the stent surface "invisible" to the blood and its components. Delayed endothelialization has been linked to late in stent thrombosis, a potentially fatal event. Thus, the use of nitric oxide eluting stent coatings has many advantages over antiproliferatives drugs, especially at the very early stages in the stent placement pathophysiology. One of the key benefits of NO is the stimulation of endothelialization which is a primary measure of healing. Thus, rapid division of endothelial cells and their rapid colonization of the stent material may be an ultimate safety feature in DES development. However, rapid division of endothelial cells is inconsistent with certain drugs used in DES, many of which have antiproliferative and antimigratory properties, and would inhibit the growth of the endothelial cell population and defeat the purpose of adding NO.

A summary of the properties of drugs commonly used in DES is listed below, and includes antiproliferatives, cytokine suppressants, antiinflammatories and others.

Paclitaxel - antiproliferative; blocks cell division Sirolimus - antiproliferative Everolimus - antiproliferative Tacrolimus - antiproliferative Zotarolimus - antiproliferative Pimecrolimus - cytokine suppressant, indirect antiproliferative ABT-578 - antiproliferative Other antiproliferative agents (e.g., cisplatin) Dexamethasone - anti-inflammatory Estradiol - hormone, pro-healing

The NSAID / COX inhibitor class (e.g. naproxen) - anti-inflammatory

Polymers and other delivery methods for nitric oxide for medical devices There are a number of delivery methods of nitric oxide through a polymer including use of small molecule N-diazeniumdiolates from a pore matrix (Reynolds et al., 2004), use of N-diazeniumdiolate polymers (5,405,919 Keefer et al, 5,525,357

Keefer et al., 6,703,046 Fitzhugh et al.), nitrosothiols (6,673,891 Stamler et al.) and nitroprusside (6,656,217 Herzog et al.). However, N-diazeniumdiolate small molecules and polymers have the potential to form carcinogenic nitrosamines (Parzuchowski et al., 2002). The nitrosothiols have been shown to be unstable and labile to standard sterilization methods, and nitroprusside is difficult to sterilize. Both nitrosothiols and nitroprusside require metabolism to release NO and are subject to tolerance formation.

Arnold et al. have previously reported C-diazeniumdiolate polymers (7,105,502; US Pat. Application 20050203069). C-daizemiumdiolate polymers were also reported by Kalivretenos et al. (US Provisional Patent Application

US60/742,264). An advantage of the latter C-diazeniumdiolate polymers is the lack of protein binding functionality.

The current invention benefits from the advantages of the related art without suffering from their shortcomings. In brief, the present invention describes, in various embodiments, compositions, materials, methods and devices whereby biphasic release of NO and antiproliferative and/or other biologically active agents from medical devices is achieved, wherein the nitric oxide is released first over a period of hours, days or weeks, followed by release of the antiproliferative agent or other biologically active agent. This temporal separation allows the NO to stimulate endothelialization of the device (e.g., stent) and surrounding tissue in the period immediately following implantation, allowing for a more natural healing and providing a device that is much more biocompatible to the particular environment within the biological tissue.

According to the present invention, a variety of techniques may be used to develop coatings that release a pulse of NO for a given period of time, which may be, for example, periods of hours, days or weeks, or any other predetermined time period suitable for a given biological environment, followed by release of an antiproliferative agent. Virtually any method that can achieve the temporal separation of release of the NO from the antiproliferative can be used in the current invention. These include:

1) Use of a controlled pore matrix to release the NO donor drug and the antiproliferative.

2) Doping of NO donor drugs into the polymer along with the antiproliferative drug and controlling release through the hydrophobicity of the polymer.

3) NO donor drug dissolved into polymer coating while the antiproliferative is suspended as a slow-dissolving microparticle, resulting in a delayed release for the antiproliferative .

4) Use of multilayer polymer that has a hydrophilic layer to allow hydrophilic NO donor drugs to be easily activated and released, over a hydrophobic coating layer that is hydrophobic to contain the hydrophobic antiproliferative drugs.

5) Use of multilayer polymer that has an NO donor drug containing outer layer and an antiproliferative drug containing inner layer.

' 6) Use of multilayer polymer that has a non-drug containing hydrophobic layer between an outer coating (hydrophilic or hydrophobic) containing the NO donor drug and an inner polymer layer containing the antiproliferative drug.

7) Use of a multilayer coating where the outer NO donor drug containing layer is an erodable or biodegradable polymer, and the inner layer contains the antiproliferative or other biologically active agent.

8) Use of a multilayer coating where both the outer NO donor drug containing layer and the inner antiproliferative or bioactive agent containing layers are erodable or biodegradable polymers or materials. 9) Co-polymerization of an antiproliferative-releasing polymer with an NO- releasing polymer. 10) Embedding an NO-releasing polymer into an antiproliferative-releasing polymer.

11) Overlaying an NO-releasing polymer over an antiproliferative-releasing polymer. 12) Use of methods where the polymer coating itself is a composition that releases NO directly from the polymer.

13) A polymer where the nitric oxide is release directly from the polymer composition.

14) Any other method known to one skilled in the art that will allow an initial release of NO for a therapeutically useful period and will delay the release of antiproliferative for that same period.

The current invention describes compositions, materials, methods and devices whereby biphasic release of NO and a antiproliferative agent or other biologically active agent from a vascular medical device is achieved, wherein the nitric oxide is released first over a period of hours, days or weeks, followed by release of the antiproliferative agent or other biologically active agent. This temporal separation allows the NO to stimulate endothelialization of the vascular medical device and surrounding tissue, allowing for a more natural healing and providing a device that is much more biocompatible. The early pulse of NO also serves to block fibrinogen/platelet adhesion/release of platelet growth factors cycle that is an early trigger of smooth muscle cell proliferation. In addition the NO reduces the infiltration of inflammatory cells to the device site and their subsequent release of smooth muscle-stimulating growth factors. The NO may also reduce additional thrombus formation and directly suppress any early proliferation of smooth muscle cells. After the NO release is completed, the antiproliferative drug or other bioactive agent begins to be released and provides a long term suppression of vascular smooth muscle cells.

A wide variety of NO donor drugs may be used in the current invention, without limitation to any particular drug, including but not limited to: C- diazeniumdiolates, N-nitroso compounds such as O-diazeniumdiolates and the N- diazeniumdiolates, nitrosothiols (e.g. SNAP), organic nitrates (e.g. nitroglycerine) and T7US2006/042376

nitrites, nitroprusside and other iron nitrosyl compounds, ruthenium/NO or other metal/NO complexes, heterocyclic N-oxides, mesoionic heterocycles, C-nitroso compounds, Oximes, N-hydroxyguanidines and N-hydroxyureas.

An exemplary embodiment of the present invention uses C-diazeniumdiolates and/or O-diazeniumdiolates as the nitric oxide donor. These compounds have distinct chemical advantages as shown in Table 1. Unlike the N-daizeniumdiolates, they do not form nitrosamines (potential carcinogens) or secondary amines (potential irritants), do not have the potential to release large amounts of cyanide (as does nitroprusside), are stable at room temperature (unlike the nitrosothiols), and give a predicable release of NO that is independent of body chemistry and disease states (unlike nitrodothiols). Furthermore, the diazneiumdiolates do not exhibit the potential for tolerance as do nitrosothiols, organic nitrates and nitroprusside.

Table 1.

Figure imgf000009_0001

After consideration of the present invention and the instant disclosure, it would be within the purview of one having ordinary skill in the art to develop coatings that release a pulse of nitric oxide for hours to days, followed by release of an antiproliferative agent. Virtually any method that can achieve the appropriate duration of release and the temporal separation of release of the NO from the antiproliferative or other bioactive agent can be used in the current invention.

One skilled in the art will realize, after consideration of the present disclosure, that there are many possible methods to achieve the current invention. The following methods are merely exemplary and represent just a few examples of some of the available methods to achieve the current invention. Many other techniques are also possible and within the scope of the present invention. Controlled Pore Matrix Methods of making matrix dosages are well known in the art and any known method of making such dosages which yields the desired release duration and separation can be used. Materials can include, for example, one or more gel forming polymers such as polyvinyl alcohol, cellulose ethers including, for example, hydroxy propyl alkyl, celluloses such as hydroxypropyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose, natural or synthetic gums such as guar gum, xanthum gum, and alginates, as well as, ethyl cellulose, polyvinyl pyrrolidone, fats, waxes, polycarboxylic acids or esters such as the Carbopol® (Noveon IP Holdings, Corporation) series of polymers, methacrylic acid copolymers, and methacrylate polymers. Other materials may include cross-linked polymers (e.g., cross-linked polystyrene). A vast variety of other materials can be used by one skilled in the art. See: Treatise on Controlled Drug Delivery, Agis Kydonieus, Ed., Marcel

Dekker, 1992.

For the purpose of the current invention, large differences in molecular size may be exploited within a controlled pore matrix, yielding differential release profiles. The large antiproliferative molecule (> 600 FW) may be contained within the small pores of the matrix and therefore its release delayed. The small nitric oxide donor molecule (~ 200 FW) may be easily released for the pores of the matrix. This differential diffusion can be further capitalized upon by incorporating the nitric oxide- releasing capability as part of the polymer composition as described in PCT Pat Application PCT/US05/000174 and US Provisional Patent Application 60/742,264, incorporated by reference herein in their entirety, thus allowing only the very small nitric oxide molecule (30 FW) to freely diffuse out of the matrix. The pore size and matrix loading parameters can be adjusted by one skilled in the art to increase or decrease the relative differences in release profile such that virtually no overlap in release is observed. It is possible to increase the size of the antiproliferative or other agent by complexing, conjugating, or other methods used by those skilled in the art, in order to decrease the rate of release. The rate of nitric oxide release from certain donors such as diazeniumdiolates can be accelerated by incorporation of acid and slowed by incorporation of base into the matrix (Zhou and Meyerhoff, 2005). Multiple layers of controlled pore matrices with different properties can be used to optimize the utility of this invention. Additional layers may also be employed to achieve separation of release profiles.

Biodegradable / erodable polymers

The present invention can also be achieved using biodegradable polymers. Generally, biodegradable polymers are designed to break down at a uniform rate due to bulk hydrolysis of the polymer chain components. Some of the more acceptable materials (e.g., polylactides, polyglycolides) degrade into smaller chains of lactic acid and glycolic acid, both biologically acceptable, and part of the metabolome of most mammals. For some materials (e.g., polyorthoesters and polyanhydrides) the degradation occurs only at the surface, resulting in a release rate that is proportional to the surface area of the polymer particle. For vascular medical device applications it is very useful to use biocompatible polymers. The present invention can be comprised of polymer(s) selected from the group including, but not limited to: poly(lactides), poly(glycolides), poly(lactide-co- glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), ρoly(alkylene oxalate)s, biodegradable polyurethanes, blends and copolymers thereof, salicylic acid polymers and derivatives, blends and co-polymers thereof.

In an exemplary embodiment of the present invention, the antiproliferative or other bioactive agent layer comprising the stent or other vascular device is formed using a first layer comprised of a polymer with a very slow degradation rate that incorporates the antiproliferative or other agent, followed by an outer layer comprised of a polymer with a degradation rate adjusted to optimize the duration of nitric oxide donor or nitric oxide release. A surface degrading polymer may be most preferred for the outer layer so that the inner layer(s) may be protected from dissolution, thus achieving temporal separation of the active agents. A thin inert layer of degradable polymer may be used between the nitric oxide-releasing outer layer and the active- agent-releasing bottom layer. The thickness or other properties of the outer layer (or any layer) may also be altered to optimize the duration of nitric oxide donor or nitric oxide release as known to one skilled in the art.

In one exemplary method of the present invention, rapamycin is intermixed with polylactic acid and the mixture is either extruded or solvent cast. This composition may then be laminated to a structural layer of like polymer not containing rapamycin using a heat or solvent lamination technique. An additional layer of intermixed polylactate and diazeniumdiolated deoxybenzoin are either extruded or solvent cast, and laminated to the layer containing rapamycin using heat or solvent lamination. In an alternative embodiment, the nitric oxide-releasing layer is comprised of any acidic polymer comprised of a C-H bond which is alpha to a carbonyl group (e.g. salicylic acid polymer, or co-polymer). The said polymer is then either extruded or solvent cast, and laminated to the layer containing rapamycin using heat or solvent lamination. The proton alpha to the carbonyl is then extracted using base and diazeniumdiolated in situ as described in US Provisional Patent Application

60/742,264. The thickness of the other layer or the duration of the in situ diazeniumdiolation step may be varied to achieve a release of nitric oxide from 1 minute to 48 hours duration, or 48 hours to 40 days duration.

Alternatively, the polylactate or other acidic polymer is diazeniumdiolated as described in US Provisional Patent Application 60/742,264, then either extruded or solvent cast, followed by lamination to the inner layer containing rapamycin using heat or solvent lamination. The thickness of the outer layer is determined by taking the dissolution rate of the diazeniumdiolated lactate, and adjusting for the duration of nitric oxide release required to achieve release for 1 min to 48 hours or from 48 hours to 40 days. One skilled in the art will realize that a plurality of materials and methods can be used to practice this embodiment of the current invention. Use of nitric oxide-releasing polymers

Another exemplary method according to the present invention would be the use of nitric oxide-releasing polymers as the outer coating layer for a vascular medical device such as those described in PCT Patent Application PCT/US05/000174 and US

Provisional Patent Application 60/742,264. The antiproliferative or other active agent 76

layer can be comprised of any suitable delivery system such as those described above or other delivery system known to those skilled in the art. The antiproliferative coated device can then be dipped, sprayed, etc., with a solution of the nitric oxide-releasing polymer (e.g. polymer or co-polymer partially comprised of vinylacetate or other acidic group) in MeOH or other suitable solvent that results in coating of sufficient thickness to achieve the desired duration of nitric oxide release of 1 min to 48 hours or 48 hours to 40 days. An alternative method to control the duration of release is by increasing the hydrophobicity of the nitric oxide-releasing polymer, for example by adding hexylmethacrylate moieties to the copolymer. Additional layer(s) may be used between the bottom and outer nitric oxide-releasing layer to control or further delay the release of the antiproliferative or other bioactive agent.

One skilled in the art will appreciate that different technologies can be separately used for the inner and outer layers, and that the teachings described are not the only techniques by which the invention can be practiced.

EXAMPLES

Strategies useful to the current invention are illustrated by, but are not limited to, the following examples.

Example 1

This example shows a rapid burst of nitric oxide release from a relatively porous outer coating matrix.

Deoxybenzoin-NONOate was doped into a thick solution of blended poly ethylvinyl acetate (60% ethyl) and poly butylmethacrylate, about 50:50 by weight. The mixture was stirred to disperse the deoxybenzoin-NONQate and a metal coupon was dip coated with the mixture and allowed to cure for 24 hrs. To determine the release of NO from the coating, the material was placed in vessel according to the method of Smith et al. (1996) and measured for the release of nitric oxide as follows: Weights of the samples are recorded and placed in 0.1 M phosphate buffer (pH 7.4) and the mixture is allowed to stand open to the air at 250C in a water bath. The buffer is then purged with argon gas via a fritted glass tube at the bottom of the vessel, such that the gaseous effluent gas is passed through a chemiluminescent NOx detector calibrated to measure NO content (ThermoEnvironmental Instruments, Franklin, MA, Model 42C chemiluminescent NOx detector). Bubbling is continued until a steady and horizontal trace is achieved, whereupon the signal is integrated over a span of several minutes. The number of integral units is converted to a value for moles of NO by comparisons with integrals obtained for certified gaseous standards of NO in helium (MG Industries, Morrisville, PA). The rate of NO release over that time increment, calculated by dividing the integrated signal by the number of minutes the integration was conducted, may be plotted versus the total elapsed time since the sample was first placed in the buffer. The release profile for this embodiment shows a rapid release of nitric oxide with a peak release of 4.5 pmol NO per cm2 per min at 4 min, followed a plateau at around 10 min of 0.1 pmole per cm2 per min that remains at that level for a duration of approximately 40 min

Example 2 This example shows a multi-day release of nitric oxide from a relatively porous outer coating matrix.

DETA-NONOate was doped into a thick solution of blended poly ethylvinyl acetate (60% ethyl) and poly butylmethacrylate, about 50:50 by weight. The mixture was stirred to disperse the DETA-NONOate and a metal coupon was dip coated with the mixture and allowed to cure for 24 hrs. The method of Smith et al. described in example 1 was used to measure the release of NO from the composition.

The NO release profile for the composition of this example shows a straight rise to a plateau at 5 min of 0.2 pmol / cm2 / min and remained essentially at this level over the first several hours. By day 3, the release rate had decayed to 0.1 pmol / cm / min and by day 6 the release rate had decayed to 0.04 pmol / cm2 / min.

Example 3

This example demonstrates the ability to release NO from a possible outer coating for at least 40 days using NO-releasing polystyrene beads embedded in a hydrophobic polymethacrylate polymer. The diazeniumdiolated polystyrene beads were made according to the method described in PCT Patent Application # 6 042376

PCT/US05/000174. The beads were embedded in a film of poly ethylvinyl acetate (60% ethyl) and polybutyl methacrylate, about 50:50 by weight as described in Examples 1 and 2. The NO release profile was determined using the method of Smith et al., 1995. The NO released was 38 fmol /cm2 / sec on day 1, and the NO release rate had decayed by 50% per day through day three, and reached a slowly decaying plateau on day 4 of 5 fmol /cm2 / sec that lasted through day 9. The rate of NO release continued to slowly decay until day 40 when the NO release rate was approximately 0.5 fmol / cm2 / sec at which point the experiment was stopped.

Example 4 - Controlled Pore Matrix Example A 1% divinyl benzene cross-linked polystyrene is swelled in anhydrous ultrapure solvent (e.g. THF) with an appropriate concentration of rapamycin. The polystyrene is filtered and the solvent is removed under vacuum. The polystyrene is then placed in a solution of nitric oxide donor in ethanol for an appropriate time period. The polystyrene is filtered and the ethanol is removed by vacuum. The polystyrene is then placed in a physiological buffer at pH 7.4 and aliquots of the buffer are taken at specific time points. The aliquots are tested for the presence of nitric oxide donor in solution (in chemical forms before and after release of nitric oxide) and rapamycin using an HPLC or other appropriate method known in the art, and the concentration of nitric oxide donor (total of before and after release chemical forms) and rapamycin are plotted over time. The degree of overlap is noted and adjustments can be made to decrease any overlap of the two drugs as well as alter the duration of nitric oxide donor release and start point for rapamycin release. Parameters that may be altered include, but are not limited to, degree of polystyrene cross-linking (i.e. increasing the degree of cross-linking will delay the rapamycin release to a greater degree that the NO donor or NO), the concentration of rapamycin loaded, the solvent used to load the nitric oxide donor (i.e a more hydrophobic solvent like THF will swell the beads allowing a greater penetration of the NO donor, resulting in a greater duration of release), the size of both the nitric oxide donor and rapamycin (by complexation, conjugation or other method), the duration of nitric oxide donor loading, and the concentration of nitric oxide donor loaded. Other methods using two layers of differentially porous matrix materials may also be used 006/042376

in the current invention, including, but not limited to, microencapsulation of the rapamycin (or other agent), or differential microencapsulation. Furthermore, certain nitric oxide donors, such as the diazeniumdiolates, can be accelerated to release NO by doping acids (preferably organic acids) into the matrix. Alternatively, the release of NO from diazeniumdiolate compounds can be slowed by incorporating base.

Example 5 - Use of a Biodegradable Coating

A coating may be prepared from hydrophilic poly(lactice-co-glycolide) polymer RG502H having free carboxyl end groups (hereinafter "unblocked-PLGA") (50:50 PLGA, 9,300 Daltons; Boehringer Ingelheim Chemicals, Inc.) or a more hydrophobic PLGA polymer having blocked carboxyl end groups (hereinafter

"blocked-PLGA") (50:50 PLGA, 10,000 Daltons; Lot #115-56-1, Birmingham Polymers, Inc., Birmingham, Ala.).

The blocked-PLGA polymer described above can be dissolved in methylene chloride or other appropriate solvent at room temperature. Paclitaxel can be added to the polymer solution and the mixture sonicated to give a homogeneous suspension.

The suspension is atomized through a sonicating nozzle on to a bed of frozen ethanol, overlaid with liquid nitrogen to form mcrospheres. The vessel containing the microspheres can be stored at -80 °C to extract the methylene chloride and then freeze-dried to give a free-flowing powder. The hydropyllic "unblocked-PLGA" is dissolved in methylene chloride or other appropriate solvent at room temperature. A small molecule nitric oxide donor (e.g., deoxybenzoin-NONOate) is added to the polymer solution and the mixture is then sonicated to give a homogeneous suspension. The suspension is atomized through a sonicating nozzle on to a bed of frozen ethanol, overlaid with liquid nitrogen. The vessel containing the microspheres is stored at -80 0C to extract the methylene chloride and then freeze-dried to give a free-flowing powder.

The powdered "blocked-PLGA" containing the paclitaxel can be pressure cast, extruded, or mixed with a fluid vehicle and cast into a device (e.g., stent). The powdered "unblocked-PLGA" containing a NO donor can then be heat laminated, for example, onto the cast of material comprised of 'blocked-PLGA'Vpaclitaxel to form a multi-layer device. 76

Example 6 - Use of Nitric Oxide-Releasing Polymers for the Outer Layer.

A delayed-release inner base coat of an antiproliferative drug (e.g., rapamycin) or other active agent is applied to a vascular medical device using a method described above or any of the methods known to one skilled in the art. An outer layer comprised of a nitric oxide-releasing polymer (e.g. , as described in PCT Patent Application

PCT/US05/000174 and US Provisional Patent Application 60/742,264) is dissolved in a solvent (e.g. MeOH) and coated unto the vascular medical device using any suitable method known to one skilled in the art (e.g., spray coated). The hydrophobicity and/or the thickness of the outer coating may be changed by changing the co-polymer composition to include more hydrophobic moieties (e.g., hexylmethacrylate to increase hydrophobicity, vinylalcohol to decrease hydrophobicity) to achieve the desired duration of nitric oxide release. Additional layers may be added between the existing layers to control and or delay the release of the antiproliferative or other bioactive agent in the inner layer of the coating.

References

Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet. 2004 Aug 14-20;364(9434):583-91. Columbo A and Iakovou I. Drug-eluting stents: the new gold standard for percutaneous coronary revascularization. Eur Heart J 200425(11):895-7.

Dal Secco D, Moreira AP, Freitas A, Silva JS, Rossi MA, Ferreira SH, Cunha FQ. Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM- 1: role of soluble guanylate cyclase, Nitric Oxide. 2006; 15(l):77-86. Dal Secco DD, Paron JA, de Oliveira SH, Ferreira SH, Silva JS, Cunha Fde Q.

Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis, Nitric Oxide. 2003; 9(3): 153-64.

Frost MC, Rudich SM, Zhang H, Maraschio MA, Meyerhoff ME. In vivo biocompatibility and analytical performance of intravascular amperometric oxygen sensors prepared with improved nitric oxide-releasing silicone rubber coating. Anal

Chem. 2002; 74(23):5942-7. Erratum in: Anal Chem. 2003 Feb 15;75(4):1037.

Hill RA, Dundar Y, Bakhai A, Dickson R, Walley T. Drug-eluting stents: an early systematic review to inform policy. Eur Heart J. 2004, 25(11):902-19.

Janero DR and Ewing JF. Nitric Oxide and Postangioplasty Restenosis: Pathological Correlates and Therapeutic Potential. Free Rad Biol Med 2000.

29(12):1199-1221.

Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK5 Virmani R. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(l): 193-202. LaI BK, Hobson RW 2nd, Goldstein J, Geohagan M, Chakhtoura E, Pappas

PJ, Jamil Z, Haser PB, Varma S, Padberg FT, Cerveira JJ. In-stent recurrent stenosis after carotid artery stenting: life table analysis and clinical relevance. J Vase Surg. 2003 Dec;38(6):l 162-8; discussion 1169.

Mooradian DL, Hutsell TC, Keefer LK. Nitric oxide (NO) donor molecules: effect of NO release rate on vascular smooth muscle cell proliferation in vitro. J

Cardiovasc Pharmacol. 1995 25(4):674-8. Morbidelli L5 Donnini S, Ziche M. Role of nitric oxide in the modulation of angiogenesis. Curr Pharm Des. 2003; 9(7):521-30.

Parzuchowski PG, Frost MC, and Meyerhoff ME. Synthesis and Characterizationof Polymethacrylate-based Nitric Oxide Donors. J Am Chem Soc 2002. 124:12182-12191.

Radomski MW5 Palmer RM5 Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987; 148(3):1482-9.

Reynolds MM5 Frost MC, Meyerhoff ME. Nitric oxide-releasing hydrophobic polymers: preparation, characterization, and potential biomedical applications. Free

Radic Biol Med. 2004. 37(7):926-36.

Smith DJ, Chakravarthy D, Pulfer S5 Simmons ML5 Hrabie JA5 Citro ML5 Saavedra JE5 Davies KM5 Hutsell TC5 Mooradian DL5 Hanson SR5 Keefer LK. Nitric oxide-releasing polymers containing the [N(O)NO]- group. J Med Chem. 1996 39(5):1148-56.

Treatise on Controlled Drug Delivery, Agis Kydonieus, Ed., Marcel Dekker, 1992.

Venturini CM, Weston LK5 Kaplan JE. Platelet cGMP, but not cAMP, inhibits thrombin-induced platelet adhesion to pulmonary vascular endothelium. Am J Physiol. 1992; 263(2 Pt 2):H606-12.

Zhou Z5 Meyerhoff ME. Polymethacrylate-based nitric oxide donors with pendant N-diazeniumdiolated alkyldiamine moieties: synthesis, characterization, and preparation of nitric oxide releasing polymeric coatings. Biomacromolecules. 2005; 6(2):780-9. Ziche M, Parenti A5 Ledda F5 Dell'Era P5 Granger HJ5 Maggi CA5 Presta M.

Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res. 1997 80(6):845-52.

Claims

What is claimed is:
I) A material for coating medical devices that comprises: one or more layers coated on a medical device and capable of releasing NO and at least one antiproliferative agent, wherein the release of the NO and the agent are substantially temporally separated.
2). The material in claim 1, wherein the medical device is a cardiac stent.
3) The material in claim 1 , wherein the NO is released by a NO donor.
4) The material in claim 3, wherein the NO donor is a C- diazeniumdiolate . 5) The material in claim 4 wherein the C-diazeniumdiolate is a modified polystyrene bead.
6) The material of claim 4 wherein the C-diazeniumdiolate polystyrene bead is embedded into a polymer.
7) The material of claim 4 wherein the C-diazeniumdiolate is a copolymer of modified vinylacetate or other acidic moiety.
8) The material of claim 1 wherein the NO release substantially occurs during the period immediately following implantation of the medical device and the antiproliferative agent release substantially occurs during the period following the NO release. 9) The material of claim 1 wherein the NO is released within a period of from 1 minute to 48 hours.
10) The material of claim 1 wherein the NO is released within a period of from 48 hours to 40 days.
I I) The material of claim 1 wherein the NO-releasing layer is selected from the group consisting of C-diazeniumdiolates, O-diazeniumdiolates, N- diazeniumdiolates, Nitrosothiols, organic nitrates and nitrites, nitroprusside and other iron nitrosyl compounds, ruthenium/NO or other metal/NO complexes, heterocyclic N-oxides, mesoionic heterocycles, C-nitroso compounds, oximes, N- hydroxyguanidines and N-hydroxyureas, and other nitric oxide releasing compounds. 12) The material of claim 1 wherein the antiproliferative agent is selected from the group consisting of paclitaxel, sirolimus, everolimus, pimecrolimus, tacrolimus, zotarolimus, dexamethasone, 17β-estradiol, and NSAID's.
13) A device comprising: a cardiac stent that provides an initial release of NO for a therapeutically relevant period and a subsequent release of an antiproliferative drug for a second therapeutically relevant period.
14) A device comprising: a cardiac stent that provides an initial release of NO for a therapeutically relevant period following implantation and that substantially delays release of an antiproliferative drug for the same period.
15) A method for coating a medical device comprising: coating the device with a first polymer layer containing an antiproliferative drug and a second polymer layer containing a NO-releasing agent. 16) A method for coating a medical device comprising: coating the stent with a first inner polymer layer containing at least one antiproliferative or anti-inflammatory drug, a second intermediate layer comprising a polymer capable of delaying the release of the antiproliferative drug from the inner layer, and a third outer layer containing a NO-releasing agent.
PCT/US2006/042376 2005-10-31 2006-10-31 Multi-phasic nitric oxide and drug co-eluting stent coatings WO2007053578A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US73141405P true 2005-10-31 2005-10-31
US60/731,414 2005-10-31
US74226405P true 2005-12-06 2005-12-06
US60/742,264 2005-12-06

Publications (2)

Publication Number Publication Date
WO2007053578A2 true WO2007053578A2 (en) 2007-05-10
WO2007053578A3 WO2007053578A3 (en) 2008-09-18

Family

ID=38006448

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/042376 WO2007053578A2 (en) 2005-10-31 2006-10-31 Multi-phasic nitric oxide and drug co-eluting stent coatings

Country Status (1)

Country Link
WO (1) WO2007053578A2 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008088507A2 (en) * 2007-01-18 2008-07-24 Boston Scientific Scimed, Inc. Blood-contacting medical devices for the release of nitric oxide and anti-restenotic agents
WO2009014829A3 (en) * 2007-07-24 2009-03-26 Mingfei Chen Methods for introducing reactive secondary amines pendant to polymer backbones that are useful for diazeniumdiolation
US7811600B2 (en) 2007-03-08 2010-10-12 Medtronic Vascular, Inc. Nitric oxide donating medical devices and methods of making same
US8021679B2 (en) 2005-08-25 2011-09-20 Medtronic Vascular, Inc Nitric oxide-releasing biodegradable polymers useful as medical devices and coatings therefore
US8158187B2 (en) 2008-12-19 2012-04-17 Medtronic Vascular, Inc. Dry diazeniumdiolation methods for producing nitric oxide releasing medical devices
US8241619B2 (en) 2006-05-15 2012-08-14 Medtronic Vascular, Inc. Hindered amine nitric oxide donating polymers for coating medical devices
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US8709465B2 (en) 2009-04-13 2014-04-29 Medtronic Vascular, Inc. Diazeniumdiolated phosphorylcholine polymers for nitric oxide release
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
WO2016025550A1 (en) * 2014-08-14 2016-02-18 Rohm And Haas Company Polymer with releasable gas
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020614A1 (en) * 2002-01-10 2005-01-27 Prescott Margaret Forney Drug delivery systems for the prevention and treatment of vascular diseases comprising rapamycin and derivatives thereof
US20050079148A1 (en) * 2001-10-04 2005-04-14 Fitzhugh Anthony L. Highly cross-linked, extremely hydrophobic nitric oxide-releasing polymers and methods for their manufacture and use
US20050113907A1 (en) * 2002-06-28 2005-05-26 Fischell David R. Method and apparatus for treating vulnerable coronary plaques using drug-eluting stents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050079148A1 (en) * 2001-10-04 2005-04-14 Fitzhugh Anthony L. Highly cross-linked, extremely hydrophobic nitric oxide-releasing polymers and methods for their manufacture and use
US20050020614A1 (en) * 2002-01-10 2005-01-27 Prescott Margaret Forney Drug delivery systems for the prevention and treatment of vascular diseases comprising rapamycin and derivatives thereof
US20050113907A1 (en) * 2002-06-28 2005-05-26 Fischell David R. Method and apparatus for treating vulnerable coronary plaques using drug-eluting stents

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8021679B2 (en) 2005-08-25 2011-09-20 Medtronic Vascular, Inc Nitric oxide-releasing biodegradable polymers useful as medical devices and coatings therefore
US8241619B2 (en) 2006-05-15 2012-08-14 Medtronic Vascular, Inc. Hindered amine nitric oxide donating polymers for coating medical devices
WO2008088507A3 (en) * 2007-01-18 2009-06-18 Liliana Atanasoska Blood-contacting medical devices for the release of nitric oxide and anti-restenotic agents
WO2008088507A2 (en) * 2007-01-18 2008-07-24 Boston Scientific Scimed, Inc. Blood-contacting medical devices for the release of nitric oxide and anti-restenotic agents
US7811600B2 (en) 2007-03-08 2010-10-12 Medtronic Vascular, Inc. Nitric oxide donating medical devices and methods of making same
WO2009014829A3 (en) * 2007-07-24 2009-03-26 Mingfei Chen Methods for introducing reactive secondary amines pendant to polymer backbones that are useful for diazeniumdiolation
US8273828B2 (en) 2007-07-24 2012-09-25 Medtronic Vascular, Inc. Methods for introducing reactive secondary amines pendant to polymers backbones that are useful for diazeniumdiolation
US8158187B2 (en) 2008-12-19 2012-04-17 Medtronic Vascular, Inc. Dry diazeniumdiolation methods for producing nitric oxide releasing medical devices
US8709465B2 (en) 2009-04-13 2014-04-29 Medtronic Vascular, Inc. Diazeniumdiolated phosphorylcholine polymers for nitric oxide release
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
WO2016025550A1 (en) * 2014-08-14 2016-02-18 Rohm And Haas Company Polymer with releasable gas

Also Published As

Publication number Publication date
WO2007053578A3 (en) 2008-09-18

Similar Documents

Publication Publication Date Title
Alexis et al. In vitro study of release mechanisms of paclitaxel and rapamycin from drug-incorporated biodegradable stent matrices
Khan et al. Drug eluting stents: developments and current status
US7846940B2 (en) Solution formulations of sirolimus and its analogs for CAD treatment
EP2114481B1 (en) Biodegradable vascular support
JP5425364B2 (en) Absorbable stent comprising a degradation control and coatings for pH neutral maintenance
CA2905640C (en) Device for local and/or regional delivery employing liquid formulations of therapeutic agents
CA2571302C (en) Drug-eluting articles with improved drug release profiles
US8003123B2 (en) Biologically absorbable coatings for implantable devices and methods for fabricating the same
US6994867B1 (en) Biocompatible carrier containing L-arginine
JP5452832B2 (en) Drug-eluting coatings for medical implants
US8007737B2 (en) Use of antioxidants to prevent oxidation and reduce drug degradation in drug eluting medical devices
US8182527B2 (en) Heparin barrier coating for controlled drug release
JP4290985B2 (en) Implant using Fk506
US20040022853A1 (en) Polymer-based, sustained release drug delivery system
US20070083258A1 (en) Intraluminal device and therapeutic agent combination for treating aneurysmal disease
US20090005861A1 (en) Stent coatings with engineered drug release rate
US9402804B2 (en) Injectable formulations of taxanes for cad treatment
US8257724B2 (en) Delivery of highly lipophilic agents via medical devices
US7217426B1 (en) Coatings containing polycationic peptides for cardiovascular therapy
US20020193475A1 (en) Biocompatible coating for a prosthesis and a method of forming the same
EP1180013B1 (en) Local drug delivery
US7229473B2 (en) Local delivery of rapamycin for treatment of proliferative sequelae associated with PTCA procedures, including delivery using a modified stent
US7799335B2 (en) Differential delivery of nitric oxide
EP1684818B1 (en) Coatings for implantable devices including biologically erodable polyesters and methods for fabricating the same
US8257725B2 (en) Delivery of highly lipophilic agents via medical devices

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06836672

Country of ref document: EP

Kind code of ref document: A2