WO2010119443A1

WO2010119443A1 - Process for electrochemical coating of conductive surfaces by organic nanoparticles

Info

Publication number: WO2010119443A1
Application number: PCT/IL2010/000299
Authority: WO
Inventors: Shlomo Magdassi; Daniel Mandler; Ido Levy
Original assignee: Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd.
Priority date: 2009-04-13
Filing date: 2010-04-13
Publication date: 2010-10-21

Abstract

An electrodeposition process is provided for depositing a film of organic nanoparticles on conductive surfaces.

Description

PROCESS FOR ELECTROCHEMICAL COATING OF CONDUCTIVE SURFACES BY ORGANIC NANOPARTICLES

FIELD OF THE INVENTION

This invention relates to electrochemical processes for the coating of surfaces.

BACKGROUND OF THE INVENTION

Coating of miniaturized metallic surfaces with functional materials is required in many industrial applications and is crucial in the field of medical devices. Some coatings are required to render such devices biocompatible while some are used as mere delivery means of pharmaceuticals to a tissue in contact with the device. As such, the protecting coating can, in principle, serve as a matrix from which the pharmaceuticals are released over a desired period of time.

An appealing approach involves the use of nanoparticles as drug carriers that can be either introduced into body fluids or attached onto medical implants. Several methods have been used for the deposition and attachment of nanoparticles onto metallic surfaces [I]; these include layer-by-layer deposition [2,3], electrophoretic deposition [4,5], electropolymerization [6,7] and spin-[8,9] and dip-coating. In most of these methodologies, the nanoparticles are incorporated into a matrix, which is usually made of an organic or inorganic polymer. The latter reduces the total fraction of the nanoparticles in the coating and therefore also decreases the loading of the drug. Hence, there is a need for developing deposition methods of carrier-free nanoparticle coatings.

Coating may be obtained by spraying the medical device with a solution of a polymer with a dissolved or dispersed drug. This process is currently employed in the constructions of drug eluting stents (DES). hi some instances, the stents are coated with a film containing a drug capable of blocking cell proliferation, and thus prevent scar- tissue-like growth that together with clots (thrombus) could otherwise block the artery.

Several FDA approved DES are available in the market, among them are the Cypher from Cordis Corporation (a Johnson & Johnson Company, approved April 2003) [10] and Taxus from Boston Scientific (approved March 2004) [H]. Both products use previously approved bare metal stents (BxVelocity and Express 2, respectively), bearing polymeric coatings which incorporate antiproliferative drugs. As may be realized from Fig. 1, stents are complex structures which require a different coating process that would be effective both in terms of the quality of the coating and in terms of the associated costs. The main processes available for applying a drug or a drug/polymer solution to stents and other miniaturized structures typically involve solution dipping, ultrasonic spray coating, painting (air brush) and/or deposition along the struts using syringes. Some techniques combine one of the deposition methods with a continuous stent rotation to eliminate excess fluid. While these conventional techniques are useful and effective, they suffer from a great variability in drug concentration, from device to device, inability to tightly control and maintain drug concentration, inability to vary drug distribution in a controlled and predetermined manner for a more desirable drug loading profile, frequent webbing between the struts and inability to control the local area density of the drug. Another issue is cost related as these conventional techniques are all very wasteful, as much of the coating material is lost in the coating process leading to a significant cost increase, as the active compounds are very expensive.

Hence, there is an unmet industrial need for developing a better method for controllable attachment and release of functional materials from metallic surfaces.

REFERENCES

[1] Nam, S. H.; Nam, H. Y.; Joo, J. R.; Back, I. S.; Park, J. S. Bulletin of the Korean Chemical Society 2007, 28(3), 397-402.

[2] Ai, H.; Jones, S. A.; Lvov, Y. M. Cell Biochemistry and Biophysics 2003, 5P(I), 23-43.

[3] Wang, Y.; Angelatos, A. S.; Caruso, F. Chemistry of Materials 2008, 20(3), 848- 858.

[4] Zhitomirsky, I. Journal of Materials Science 2006, 41(24), 8186-8195.

[5] Umeyama, T.; Fujita, M.; Tezuka, N.; Kadota, N.; Matano, Y.; Yoshida, K.; Isoda, S.; Imahori, H. Journal of Physical Chemistry C 2007, 111(30), 11484-11493.

[6] Korkut, S.; Keskinler, B.; Erhan, E. Talanta 2008, 76(5), 1147-1152.

[7] Do Carmo, D. R.; De Castro, G. R.; Martines, M. A. U.; Dias, N. L.; Stradiotto, N. R. Materials Research Bulletin 2008, 43(12), 3286-3296.

[8] Belot, C; Filiatre, C; Guyard, L.; Foissy, A.; Knorr, M. Electrochemistry Communications 2005, 7(12), 1439-1444. [9] Chambers, S. A. Surface Science Reports 2006, 61 (8), 345-381.

[10] New Device Approval — Cypher Sirolimus-eluting Coronary Stent. Food and Drug Administration.

[11] New Device Approval — P030025 — TAXUS™ Express2™ Paclitaxel- Eluting Coronary Stent System. Food and Drug Administration.

[12] Gill, S.; Lobenberg, R.; Ku, T.; Azarmi, S.; Roa, W.; Prenner, EJ. Journal of Biomedical Nanotechnology 2007, 3, 107-119.

[13] Moinard-Checot, D.; Chevalier, Y.; Briancon, S.; Fessi, H.; Guinebretiere, S. Journal ofNanoscience and Nanotechnology 2006, 6, 2664-2681.

[14] Shacham, R.; Avnir, D.; Mandler, D. Adv. Mater. 1999, 11, 384.

[15] Shacham, R.; Avnir, D.; Mandler, D. J. Sol-Gel Sci. Tech. 2004, 31, 329.

[16] Shacham, R.; Avnir, D.; Mandler, D. Chem. Eur. J 2004, 10, 1936.

[17] Walcarius, A.; Mandler, D.; Cox, J.A.; Collinson, M.; Lev, O. J. Mater. Chem. 2005, 15, 3663.

SUMMARY OF THE INVENTION

The present invention concerns a process of coating a conducting metal surface by charged organic nanoparticles using a low potential (below ±10 V) or current. The process is based on the application of electrical current that alters the pH in the vicinity of a conducting surface. The change in the pH triggers coalescence of charged particles dispersed in a solution and causes their precipitation onto the electrode surface (Fig. 2). This novel approach permits the electrochemical coating of a conductive object, such as a medical implant, of a variety of nanoparticles that are either composed of active materials or are preloaded with active materials, as defined herein below.

In one aspect of the invention, there is provided a process for electrochemical deposition of a film of organic nanoparticles, e.g., charged nanoparticles, on a conductive surface, said process comprising contacting said conductive surface with a composition, i.e., a dispersion of organic nanoparticles, under electrochemical conditions, permitting deposition of said nanoparticles onto said conductive surface, to thereby obtain a surface coated with said nanoparticles.

In some embodiments, the process comprises:

(i) providing a conductive surface; - A -

(U) providing a dispersion of organic nanoparticles in a liquid medium

(herein a "liquid dispersion");

(iii) contacting said surface with said dispersion; and

(iv) applying a low voltage (below ±10 V) to said surface in contact with the nanoparticles, thereby inducing formation of a film of nanoparticles on said surface.

The "dispersion" or "composition", with which the conductive surface is brought into contact, is a dispersion of the organic nanoparticles and optionally at least one additive, in at least one liquid medium, said medium may be aqueous or nonaqueous. The medium may be a buffer. The at least one additive may be an electrolyte, a wetting agent, such as Tween 20, a dissolved polymer, such as polyacrylic acid salt, a co-solvent, e.g., an organic solvent such as an alcohol (methanol, ethanol), a ketone (acetone), and a surfactant, e.g., an unsaturated long-chain carboxylate (sodium oleate) and various phospholipids.

In some embodiments, the co-solvent is at least one ketone, e.g., acetone. In other embodiments, the co-solvent is a mixture of two or more solvents, one of which optionally being a ketone. In further embodiments, the ketone is acetone or a mixture thereof with an alcohol, such as ethanol, and/or with a chlorinated solvent such as dichloromethane.

In other embodiments, the dispersion is an aqueous composition comprising water, at least one surfactant such as sodium oleate, an organic co-solvent and a base or an acid.

In some embodiments, the conductive surface is immersed in the liquid dispersion prior to and throughout the electrochemical process. Thus, in other embodiments, the process comprises:

(i) providing a conductive surface;

(H) providing an aqueous liquid dispersion of organic nanoparticles;

(iii) immersing said surface in the liquid dispersion, optionally also comprising at least one additive;

(iv) applying a voltage to said surface being immersed in the dispersion, thereby inducing formation of a film of nanoparticles on said surface.

As stated hereinbefore, the coating or film forms on the conductive surface following the induction of an electrochemical reaction on the surface to be coated. The induction of the electrochemical reaction is typically achieved by applying a voltage to the surface while in contact with the dispersion. The pH at the vicinity of the surface changes due to the applied potential.

In a typical method, a DC power supply, the positive output lead is electrically connected to the surface to be coated through one or more contacts. The negative output lead of the power supply is electrically connected to the anode located in the plating solution comprising the charged organic nanoparticles, as detailed herein. During electrodeposition, power supply biases the surface to provide a negative potential relative to the anode, causing electrical current to flow from the anode to the surface. This causes an electrochemical reaction on the surface to be coated which results in the deposition of nanoparticles on the surface. It should be emphasized that the application of a negative potential to the surface to be coated is also possible providing that the nanoparticles are positively charged.

The term "contacting" or any lingual variation thereof refers within the context of the present invention to having the surface and the composition in intimate proximity to allow electrodeposition, i.e., the formation of a coating film on the surface. Generally, the applied voltage is a low voltage not exceeding a few volts in its absolute value (<10 V).

In some embodiments, said voltage not exceeding a few volts in its absolute value is a voltage between (-10) V and (+10) V versus Ag/AgBr, in some embodiments- between (-7) V and (+7) V, in other embodiments- between (-3) V and (+3) V, and in other embodiments- between (-1.4) V and (+1.4) V. In other embodiments, the voltage is between (-1.0) V to (+1.0) V. The voltage is typically applied for a period of from about 5 minutes to about 60 minutes, at room temperature (23-27°C) or at any other temperature below or above room temperature.

The film of nanoparticles, which forms on the surface, is composed of a layer made of discrete particles. As it may be desired to create a homogenous layer, the process of the invention may further comprise the subjecting of the coated surface to such conditions, e.g., sintering, which favor the formation of a continuous layer by particle coalescence. This can be achieved, for example, in case of polymeric particles, by increasing the temperature above the Tg of the organic polymer, or by adding a coalescent agent which causes coalescence or fusion of the nanoparticles, thus forming a homogenous coalesced layer. Desirably, the further step does not harm in any way the active material being the nanoparticles themselves or the material contained therein, or embedded there between.

The "organic nanoparticles" employed in the formation of the coating or film on top of the conductive surface are any carbon-based nanoparticles, which by themselves may be active materials or which contain, embed or are coated with one or more active material. The nanoparticles and/or the active material may also be in the form of a polymer, either as such or as a carrier of an active material. Where the organic nanoparticles are polymers, the term also refers to homopolymers, copolymers, such as for example, block, graft, random and alternating copolymers as well as terpolymers, further including their derivatives, combinations and blends thereof.

Furthermore, the term "polymer" includes in addition to the above all geometrical configurations of such structures including linear, block, graft, random, alternating, branched structures, and combination thereof. Non-limiting examples of organic polymers are polylactic acid (PLA), polycapro lactone, polystyrene, ethyl cellulose and others such as PLGA.

The nanoparticles are pH responsive (also referred here as "pH sensitive") and are typically less than 200 run in size. In some embodiments, the nanoparticle average size ranges from 20 and 200 run. In other embodiments, the nanoparticle average size ranges from 20 to 150 nm. In further embodiments, the nanoparticle average size ranges from 150 to 200 nm. In yet additional embodiments, the nanoparticle average size ranges from 150 to 190 nm.

The nanoparticles may be mono-dispersed, having a single shape and narrow size distribution or may be a mixture of nanoparticles in a plurality of shapes (spherical, elongated, pronged, ellipse) with a wide range of size distributions.

In some embodiments, the dispersion comprises a mixture of two or more different populations of nanoparticles, each population being different from the other by at least one of size, shape, material and chemical or physical characteristics. In other embodiments, the populations may vary in whether or not they contain, embed or are coated with at least one active material, in the identity of the active material and in its concentration. The nanoparticles may be core-shell or non-core-shell structures.

The organic nanoparticles are typically polycharged nanoparticles, namely having a plurality of positive or negative charges, which are pH dependent. Non- charged nanoparticles may be provided with surface charges by coating with polyelectrolytes such as cationic or anionic polyelectrolytes, by salts of fatty acids or by reacting pH-sensitive groups on the surface of the nanoparticles with either a base or an acid. The pH-sensitive groups may be selected amongst carboxylic acids, sulfates, phosphates, amines and many others.

Alternatively or in addition, the nanoparticles may be functionalized. In some embodiments, the nanoparticles are functionalized with pH-sensitive groups, as defined, which may be subsequently reacted to induce charge.

In some embodiments, the nanoparticles are of a material having a plurality of acidic groups (such as carboxylic acids, sulfates, phosphates) and charge is induced by forming the nanoparticles or reacting said nanoparticles under basic conditions, e.g., in the presence of at least one base, such as NaOH. In other embodiments, the nanoparticles are of a material having a plurality of basic groups (such as amine groups) and charge is induced by forming the nanoparticles or reacting the nanoparticles under acidic conditions, e.g., in the presence of at least one acid, such as HCl.

In some embodiments, the counterions of the charged nanoparticles are replaced subsequent to charge formation by adding a salt. The counterion may be selected from polymers, dendrimers, molecular ions and metal ions.

The nanoparticles are pH responsive, e.g. the number of charges per particle can be controlled by controlling the pH in which the particles are dispersed in.

In some embodiments, the nanoparticles are of PLA and charge is induced by forming the charged PLA nanoparticles in a basic medium, e.g., aqueous NaOH solution. By a typical method, the particles are formed in the presence of a stabilizer which is pH responsive, such as sodium oleate. At a pH higher than 6, the particles are negatively charged, therefore upon applying a potential during the coating process, the pH at the vicinity of the surface decreases, leading to aggregation of the particles onto the surface.

The organic nanoparticles may be prepared by any method known in the art; such methods are, for example, emulsion polymerization, suspension polymerization, solvent precipitation or emulsion/solvent evaporation methods. Typically, in the latter approach an oil-in-water nanoemulsion is prepared, while using sodium oleate as the emulsifϊer (or with combination with other surfactants), in which the oil phase is a volatile water-immiscible solvent, containing the active material, with or without a polymer. Evaporation of the solvent from the emulsion leads to a dispersion of nanoparticles in water.

In some embodiments, the surface is coated with nanoparticles of organic polymers so as to protect the surface from the environment. Such coating may be required either for coating a surface which is not biocompatible with a biocompatible polymer, or for protecting sensitive conductive surfaces form harsh conditions.

In some embodiments, the nanoparticles are composed of an active material. In other embodiments, the nanoparticles are embedded in, impregnated with, or coated with an active material. In further embodiments, the nanoparticles are of a polymeric material.

In some embodiments, the active material is released from the nanoparticles by leeching, due to the disintegration of the nanoparticles (for example if they are biodegradable), or by any other mechanism, e.g., involving the rapture of the nanoparticle surface (e.g., shell).

The "active materiaF is any material that is characterized by at least one desired functional or structural attribute rendering an effect, which may be therapeutic, diagnostic, such as an anti-corrosive, anti-fouling activity and the like. Where the coating is for a medical device, the active material is typically at least one drug or a diagnostic agent with or without a polymer. The at least one drug may be selected, in a non-limiting fashion amongst analgesic/antipyretic agents, antiasthamatic agents, antibiotic agents, antidepressant agents, antidiabetic agents, antifungal agents, antihypertensive agents, anti-inflammatory agents, antineoplastic agents, antianxiety agents, immunosuppressive agents, antimigraine agents, sedative/hypnotic agent, antipsychotic agents, antimanic agents, antiarrhythmic agents, antiarthritic agents, antigout agents, anticoagulant agents, thrombolytic agents, antifibrinolytic agents, antiplatelet agents, antibacterial agents, antiviral agents, antimicrobial agent, anti- infective agents and any combination of any of the non-limiting agents listed.

In some embodiments, the surface is that of a stent and the drug is an antiproliferative drug or an immunosuppressant, i.e., to prevent restenosis. Non-limiting examples of such drugs are sirolimus, rapamycin and paclitaxel, an antiproliferative drug. In other embodiments, said medical implant is a stent or an orthopedic device such as a screw or nail and the nanoparticles may be composed of or comprise at least one drug selected from an osteogenic material, a growth factor and an antibiotic.

Where the coating is for the prevention of corrosion the active material may be an anticorrosive agent, and where the coating is for prevention of fouling the active material maybe an antibiotic, anti-fungal, or any agent for preventing bio-film formation.

The organic nanoparticles may be core-shell structures, where the core may be empty or contain at least one substance or a mixture of substances. The nanoparticles may contain a substance selected from a drug, filler, a metal, a metal oxide, a metal salt, a metal particulate, a reinforcing material, a colorant, a fluorescent material, a magnetic material and a semiconductive material.

The drug may be selected from analgesic/antipyretic agents, antiasthamatic agents, antibiotic agents, antidepressant agents, antidiabetic agents, antifungal agents, antihypertensive agents, anti-inflammatory agents, antineoplastic agents, antianxiety agents, immunosuppressive agents, antimigraine agents, sedative/hypnotic agent, antipsychotic agents, antimanic agents, antiarrhythmic agents, antiarthritic agents, antigout agents, anticoagulant agents, thrombolytic agents, antifibrinolytic agents, antiplatelet agents, antibacterial agents, antiviral agents, antimicrobial agent, anti- infective agents and any combination of any of the non-limiting agents listed.

The term "conductive surface" refers to the surface as a whole or to at least a portion thereof (on which coating is desired) that is conductive, hi cases where the surface is conductive only in specific regions thereof, the electrodeposition will be affected at the conductive regions only. Surfaces which are non-conductive may be coated with a conductive layer, for example by electroless processes, before electrodeposition. As a person skilled in the art would recognize, the term "conductive" refers generally to the ability of the surface to conduct electric current. The conductivity of surfaces may be measured according to methods known in the art. The conductive surface to be coated according to the invention may be a surface of any device, structure, article, or element. The surface may be flat, smooth, coarse, round, a three- dimensional surface, inner and/or outer surfaces, a surface having regions of restricted access and cavities, multilayered surfaces and a surface of any thickness, constitution and size. The conductive surfaces may be for example of metallic materials or alloys such as, but not limited to, stainless steel (316L), MP35N (an alloy of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum), MP20N (an alloy of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum), EL ASTINITE (Nitinol), cobalt- chromium alloys (e.g., ELGILOY), tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as platinum-iridium alloy, indium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys, copper, graphite, or combinations thereof. Semiconductive or superconductive compounds may also serve as conductive surfaces suitable for the electrodeposition of the invention. Devices made from bioabsorbable or biostable polymers can also be used with the embodiments of the present invention, provided that at least a portion thereof to be coated is conductive.

In some embodiments, the surface is a stainless steel (316L) surface.

In other embodiments, the surface is a metallic surface, such as an indium-tin oxide (ITO) surface or a gold surface.

The conductive surface to be coated may be a surface of any device, structure, article, or element having at least one of conductive wire, or sheet. The surface may be wholly conductive or conductive at certain regions and thus may be fully coated or coated at the conductive regions only.

Non-limiting examples of devices, structures, articles, and elements having such surfaces are metals wires, metal sheets, metallic surfaces of electronic devices, patterned surfaces, electric elements, medical devices, medical implants, household appliances, refractive elements, structures requiring insulation, and containers, parted involved in water processing /transport (pipes, filters, pumps), parts involved in biological processes such as in bioreactors.

In some embodiments, the surface is the surface of a medical device or an implant.

As a person skilled in the art would recognize, a medical implant is a structure which may be implanted into the body of an animal, e.g., non-human or human. The structure may be implanted in the body of the subject during a medical procedure which purpose may be the treatment or prevention of a disease or disorder or the diagnosis of a condition. The implant may also be one which is used as a vehicle for providing therapy. The implant may act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of a passageway, inserted through small vessels, such as via catheters, and then expanded to a larger diameter once it is at the desired location. Non-limiting examples of such medical implants are a stent, an artificial heart valve, a cerebrospinal fluid shunt, a pacemaker electrode, an axius coronary shunt, an endocardial lead, an orthopedic device, and a vessel occlusion device.

In some embodiments, the surface to be coated according to the invention is the surface of a medical implant, and said organic nanoparticles may comprise an active material, e.g., a drug.

In some embodiments, the implant is a stent.

In some other embodiments, the orthopedic device is selected from a fixation device, a bone screw, a wire, a plate, a rod, a pin, and a nail.

The invention also provides a surface coated with electrodeposited film of organic nanoparticles.

The film is between about 1 nanometer to 100 micrometer thick. In some embodiments, the electrodeposited film is a homogenous film or a heterogeneous film.

In some embodiments, the film, as characterized herein, is obtained by an electrochemical deposition process according to the invention. In further embodiments, the surface is a surface of a device, structure, article, or element. In some embodiments, the surface is the surface of a stent.

As a person versed in the art would realize, the film formed need not cover the full surface of the device. Additionally, the film may be of any size and shape and may have an overall shape which is different from the shape of the surface which it covers. The film may be of any size, hi some embodiments, the surface area which the film occupies is smaller as compared to the surface of the device.

The present invention further concerns a conductive surface coated by a layer of organic nanoparticles obtainable by the process of the present invention. Where the present invention concerns also a step of sintering to achieve a coalescent film of nanoparticles, the invention is also directed to such conductive surfaces.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: Fig. 1 is a prior art picture of a commonly available stent demonstrating its complex structure.

Fig. 2 depicts in general terms, and without being limited to any one particular mechanistic detail, the process of the invention.

Fig. 3 presents the Zeta-potential as a function of pH.

Figs. 4A-C are SEM image at different magnifications of the electrodeposited nanoparticles: Fig. 4 A and 4B as deposited; and Fig. 4C after heating at 110°C for 10 minutes.

DETAILED DESCRIPTION OF EMBODIMENTS

Electrochemistry is concerned with charge transfer (electron and ions) across interfaces. Charge transfer is limited to a few nanometers from the electrode surface and therefore, if this process results in the formation of an insoluble layer, the latter is expected to follow very closely the external morphology of the electrode. Therefore, coating of a conducting medical device by electrochemistry should provide a superior method for obtaining homogeneous, well-controlled nanometric films on complex miniaturized structures, such as stents. Yet, electrochemical coating has so far been utilized in the making of metal or metal oxide layers or conducting and non-conducting organic polymers, hi these cases the precursors for the coating layers are dissolved ions or monomers. There is, however, a great advantage if coating is made of preformed organic nanoparticles loaded with active materials.

The use of organic nanoparticles as drug delivery systems is well developed [12,13]. Besides substantial academic activity in this research field, there already exist commercial products based on such nanoparticles. Usually, the nanoparticles are made by solvent precipitation or emulsion/solvent evaporation methods. Typically, in the latter approach an oil-in-water nano-emulsion is prepared, in which the oil phase is a volatile water immiscible solvent. In case that a water insoluble drug and a polymer are dissolved within the droplets, evaporation of the solvent leads to formation of a dispersion of drug-loaded polymeric nanoparticles. Thus, using an electrochemical coating method for attaching drug-loaded organic nanoparticles provides a means for the controlled and localized release of the active materials from the coating.

Electrochemical deposition can be divided into two main approaches. The first involves the reduction or oxidation of a precursor making it less soluble, thus precipitating onto the electrode surface. The second approach is an indirect method whereby a change in the environment condition driven by electrochemistry, causes the precipitation of the coating precursor.

Recently, the inventors of the present invention have reported the electro- assisted deposition of sol-gel materials using the second approach [14,15,16,17]. Specifically, the application of electrical current caused a local change of pH (Eq. 1-2) on the electrode surface, which catalyzed the condensation of hydrolyzed sol-gel precursors.

H₂O + e^~ → OH^~ +-H₂ (Eq. 1)

H₂ 2O → - ₂ O₂2 + 2e^~ +2H⁺ (^EΦ ²)

The importance of this invention lies in the development of a new concept for preparing functional controllable coatings composed of organic nanoparticles, preferably without the need for a soluble polymer as a binder. This concept is very appealing for high throughput industrial production of metallic devices with complex structure, due to the advantages that electrochemistry provides. Moreover, the proposed process is highly generic, may be easily tailored for various conducting surfaces and nanoparticles loaded with active molecules. In addition, the process employs potentials which are much lower than those applied in the conventional electrophoretic deposition (EPD) processes (hundreds of volts), and does not cause any release of oxygen or hydrogen as in the case of EPD. Finally, a great variety of applications in the fields of medicine, antifouling, corrosion inhibition, etc may be envisioned.

Specifically, and as an example- pH sensitive polystyrene nanoparticles were synthesized using sodium oleate following the emulsion-polymerization method. The average size of the nanoparticles was ca. 70 run. The zeta-potential at pH 8.0 was -60 mV. Preliminary bulk experiments showed that coagulation occurs at pH~5-6. This is in complete agreement with the zeta-potential measurements shown in Fig. 3. As expected, due to the fatty acid salts the particles have high negative zeta-potential. Upon decrease of pH the particles become less charged, in the pH range close to the pK of the acid. The cyclic voltammetry carried out with ITO indicated that water oxidation commences at potentials more positive than 2.0 V vs. Ag/AgCl. Therefore, a constant potential of 2.0 V vs. Ag/AgCl was applied to an ITO electrode that was immersed in the dispersion of the polystyrene particles (1% w/w) and 0.05 M Na₂SO₄ as a supporting electrolyte. It was evident that a white deposit was formed on the ITO surface. Blank experiment clearly proved that the potential was essential for deposition. As shown in Fig. 4 (film after drying for 1 hr at room temp) the electrochemically deposited coating is composed of individual particles. It is worth mentioning that cracks are observed at low magnification. These are formed due to capillary forces during the drying process. Thermal treatment above Tg of polystyrene resulted in the formation of a transparent defect-free film (Fig. 4C).

A special feature of the nanoparticles is their ability to aggregate as a response to pH change. In the following examples, the preparation of biodegradable polymers is described, which polymers were tailored for aggregation at a low pH. The nanoparticles were stabilized by a fatty acid salt. At a high pH the particles are negatively charged and therefore the dispersion of the particles is stable. Upon applying a potential, the pH in the vicinity of the surface decreases, the carboxylic groups are not ionized and therefore the particles become un-charged. At this stage, there is no barrier for aggregation of the particles, and therefore a layer of aggregated particles is formed onto the substrate surface. Obviously, stabilizers other than the fatty acid soaps may be utilized, provided they lead to aggregation upon pH increase or decrease.

EXAMPLE 1

Preparation of polylactic acid (PLA) nanoparticles using acetone

The diffusing phase was formed by polymer (43.9 mg) dissolution in acetone (7.5 ml). This phase was added dropwise to the dispersing phase consisted of water (TDW, 20 ml) containing sodium oleate (22.2 mg) and NaOH (0.3mg) while applying continuous moderate stirring. The dispersion of PLA nanoparticles thus obtained was stirred for one hour. For the removal of the organic solvent, the dispersion was then evaporated for 2 hours at room temperature using a rotary evaporator. The mean particle diameter is 153 nm. EXAMPLE 2

Preparation of PLA nanoparticles using acetone-ethanol

PLA (47.1 mg) was added to acetone (1.5 ml) and left to dissolve for one hour. The organic phase was formed by dropwise addition of the prepared solution to ethanol (3 ml). This phase was added dropwise to the dispersing phase consisted of water (TDW, 20 ml) containing sodium oleate (16.4 mg) and NaOH (0.2 mg) while applying continuous moderate stirring.

These dispersions of PLA nanoparticles thus obtained were stirred for one hour. For the removal of the organic solvents, the dispersion was then evaporated for 2 hours at room temperature using a rotary evaporator. The mean particle diameter is 170 run.

EXAMPLE 3

Preparation of PLA nanoparticles using dichloromethane-acetone

PLA (50.5 mg) was dissolved in dichloromethane (0.5ml). The diffusing phase was formed by the addition of acetone (7.5 ml) to the polymer solution. This phase was poured to the dispersing phase consisting water (TDW, 20 ml) containing sodium oleate (17.6mg) and NaOH (0.2 mg) while applying continuous moderate stirring. The dispersion of PLA nanoparticles thus obtained was stirred for one hour. For the removal of the organic solvents, the dispersion was then evaporated for 2 hours at room temperature using a rotary evaporator. The mean particle diameter is 187 run.

Claims

CLAIMS:

1. A process for electrochemical deposition of a film of organic nanoparticles on a conductive surface, said process comprising contacting said conductive surface with a composition of organic nanoparticles, under such electrochemical conditions permitting deposition of said nanoparticles onto said conductive surface, to thereby obtain a surface coated with a film of said nanoparticles.

2. The process according to claim 1, comprising: (i) providing a conductive surface;

(ii) providing a dispersion of organic nanoparticles in a liquid medium; (iii) contacting said surface with said dispersion; and (iv) applying a low voltage to said surface in contact with the nanoparticles, thereby inducing formation of a film of nanoparticles on said surface.

3. The process according to claim 2, wherein said low voltage is a voltage below ±10 V.

4. The process according to claim 1 or 2, wherein said composition is a dispersion of the organic nanoparticles and optionally at least one additive, in at least one liquid medium.

5. The process according to claim 4, wherein said medium is selected from an aqueous and non-aqueous medium.

6. The process according to claim 5, wherein said aqueous medium is a buffer.

7. The process according to claim 4, wherein said at least one additive is selected from an electrolyte, a wetting agent, a dissolved polymer, a co-solvent and a surfactant.

8. The process according to claim 7, wherein said co-solvent is an organic solvent selected from an alcohol and a ketone.

9. The process according to claim 7, wherein said surfactant is selected amongst unsaturated long-chain carboxylates and phospholipids.

10. The process according to claim 1, wherein said composition is aqueous dispersion comprising water, at least one surfactant, an organic co-solvent and a base or an acid.

11. The process according to claim 1, wherein the conductive surface is immersed in the composition prior to and throughout the electrochemical process.

12. The process according to claim 11, comprising: (i) providing a conductive surface;

(ii) providing an aqueous liquid dispersion of organic nanoparticles; (iii) immersing said surface in the liquid dispersion, optionally also comprising at least one additive;

13. The process according to 12, wherein the application of a voltage to the surface while in contact with the dispersion causes a change in the pH at the vicinity of the surfaces.

14. The process according to any of the preceding claims, wherein the applied voltage is a voltage not exceeding a few volts in its absolute value (<10 V).

15. The process according to claim 14, wherein said voltage is between (—10) V and (+10) V versus Ag/AgBr.

16. The process according to claim 14, wherein said voltage is between (-7) V and (+7) V, between (-3) V and (+3) V, or between (-1.4) V and (+1.4) V.

17. The process according to claim 14, wherein said voltage is between (-1.0) V to (+LO) V.

18. The process according to claim 1, wherein said organic nanoparticles are nanoparticles of an active material.

19. The process according to claim 1, wherein said organic nanoparticles contain, embed or are coated with one or more active material.

20. The process according to claim 1, wherein said organic nanoparticles are polymers.

21. The process according to claim 20, wherein said polymers are selected from homopolymers and copolymers.

22. The process according to claim 20, wherein said polymers are selected from block, graft, random and alternating copolymers, terpolymers, their derivatives, combinations and blends thereof.

23. The process according to claim 20, wherein said polymers are selected from polylactic acid (PLA), polycapro lactone, polystyrene, and ethyl cellulose.

24. The process according to claim 23, wherein the polymer is PLA.

25. The process according to claim 1, wherein said organic nanoparticles are pH responsive.

26. The process according to claim 1, wherein said organic nanoparticles are less than 200 nm in size.

27. The process according to claim 26, wherein the nanoparticle average size ranges from 20 and 200 nm.

28. The process according to claim 26, wherein the nanoparticle average size ranges

29. The process according to claim 26, wherein the nanoparticle average size ranges

30. The process according to claim 26, wherein the nanoparticle average size ranges

31. The process according to claim 1, wherein said nanoparticles are selected amongst polycharged nanoparticles, having a plurality of positive or negative charges.

32. The process according to claim 31, wherein the charged nanoparticles are associated with pH-sensitive groups selected amongst carboxylic acids, sulfates, phosphates, and amines.

33. The process according to claim 18, wherein said active material is selected amongst anti-corrosive materials, anti-fouling materials, drugs and diagnostic agents.

34. The process according to claim 33, wherein said drug is selected amongst analgesic/antipyretic agents, antiasthamatic agents, antibiotic agents, antidepressant agents, antidiabetic agents, antifungal agents, antihypertensive agents, anti- inflammatory agents, antineoplastic agents, antianxiety agents, immunosuppressive agents, antimigraine agents, sedative/hypnotic agent, antipsychotic agents, antimanic agents, antiarrhythmic agents, antiarthritic agents, antigout agents, anticoagulant agents, thrombolytic agents, antifibrinolytic agents, antiplatelet agents, antibacterial agents, antiviral agents, antimicrobial agent, anti-infective agents and any combination of any of these agents.

35. The process according to claim 34, wherein said drug is an antiproliferative drug or an immunosuppressant.

36. The process according to claim 19, wherein said active material is contained within said organic nanoparticles.

37. The process according to claim 1 , wherein said conductive surface is a metallic surface or an alloy thereof.

38. The process according to claim 37, wherein said metal or alloy are selected from stainless steel, MP35N, MP20N, ELASTINITE, cobalt-chromium alloys, tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys, platinum- indium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium- based alloys, copper, graphite, or combinations thereof.

39. The process according to claim 37, wherein said conductive surface is a semiconductive or superconductive surface.

40. The process according to claim 38, wherein said surface is a stainless steel (316L) surface.

41. The process according to claim 38, wherein said surface is an indium-tin oxide (ITO) surface or a gold surface.

42. The process according to claim 1, wherein said conductive surface is of a device, a structure, an article, or an element having at least one of conductive wire, or sheet.

43. The process according to claim 42, wherein the surface is of metals wires, metal sheets, metallic surfaces of electronic devices, patterned surfaces, electric elements, medical devices, medical implants, household appliances, refractive elements, structures requiring insulation, and containers, parted involved in water processing /transport (pipes, filters, pumps) and bioreactors.

44. The process according to claim 1, wherein said conductive surface is the surface of a medical device or an implant.

45. The process according to claim 44, wherein said medical device or implant is selected from a stent, an artificial heart valve, a cerebrospinal fluid shunt, a pacemaker electrode, an axius coronary shunt, an endocardial lead, an orthopedic device, and a vessel occlusion device.

46. The process according to claim 1 , wherein the surface to be coated is the surface of a medical implant, and said organic nanoparticles comprise a drug material.

47. The process according to claim 45 or 46, wherein said medical device is a stent.

48. The process according to claim 45 or 46, wherein said medical device is an orthopedic device being selected from a fixation device, a bone screw, a wire, a plate, a rod, a pin, and a nail.

49. The process according to claim 1, further comprising the step of sintering the nanoparticles film.