Patent Application
20110159069
The invention pertains to medical implant devices, implantable stent devices, and methods of making medical implant devices.
Many types of medical implant devices are commonly utilized in modern medicine. Some of these devices can have drawbacks such as causing, allergic reaction or triggering blood clot formation. In implant devices such as stents, where the purpose of the device is to maintain an open artery or vein, the formation of a blood clot is contrary to the purpose of the device and can have negative effects which can even be life threatening.
Antithrombotic agents are of interest to utilize in conjunction with medical implant devices. Naturally occurring proteins that have antithrombotic or anticoagulation activity and can thereby alleviate blood clot formation include, for example, heparin. Heparin is known to act by binding to antithrombin III and inactivating thrombin. Recently, heparin has been utilized in conjunction with stents in attempt to prevent clot formation. However, heparin is mobile within the body and is able to diffuse away from the site of the stent. Accordingly, the effect of heparin under these circumstances is very short term. On the other hand, long term as well as short term effectiveness is desirable to deter clot formation and occlusion of the stent or blood vessel.
It is desirable to develop alternative implant devices and methods of forming implant devices to address these issues.
In one aspect, the invention pertains to a medical implant device comprising a device substrate having an oxidized surface with a silane derivative coating covalently bonded to the oxidized surface. A bioactive agent is covalently bonded to the silane derivative coating.
In one aspect, the invention pertains to an implantable stent device comprising a stent core having an oxidized surface with a layer of silane derivative covalently bonded to the oxidized surface. A spacer layer comprising polyethylene glycol (PEG) is covalently bonded to the layer of silane derivative and a protein is covalently bonded to the PEG.
In another aspect, the invention pertains to a method of making a medical implant device. A device substrate having a surface is provided. The surface is oxidized to produce an oxidized surface which is reacted with derivitized silane to form a silane coating over the surface. The coating is covalently bonded to the surface. A bioactive agent is then covalently bonded to the silane coating. In particular instances, an additional coating of bio-absorbable polymer and/or pharmaceutical agent may be deposited over the bioactive agent.
One embodiment provides a medical implant device comprising at least one silane derivative covalently bonded to a surface of the device and a bioactive agent covalently bonded to the at least one silane derivative.
In one embodiment the surface may comprise at least one oxidized site wherein the at least one silane derivative is covalently bonded to the at least one oxidized site.
In another embodiment the surface comprises a plurality of oxidized sites wherein a plurality of silane derivative moieties are covalently bonded to the oxidized sites and a plurality of bioactive agent molecules are covalently linked to the silane derivative moieties thereby forming the surface a layer of silane derivative moieties covalently bonded to biological agent molecules.
In one embodiment the surface is a polymer surface having a moiety forming a covalent bond with the silane derivative. The silane derivative and the polymer surface may be coupled through an organosilane linkage, for example a dialkoxysilane or a monoalkosysilane. The surface may comprise a natural polymer selected from cellulose, starch (amylose and amylopectin), proteins, silk, spider webs, polyhydroxyalkanoates, deoxyribonucleic acid (DNA), natural rubber, and polysacharides.
In one embodiment the device is a stent. The stent comprises a layer formed by biological agent covalently bonded to silane derivative moieties covalently bonded to a surface of the stent.
In one embodiment the stent further comprises a plurality of layers that form a laminate coating on said stent; wherein at least one of said layers comprises a bio-absorbable polymer and at least one of said layers comprises one or more active agents; wherein at least a portion of the active agent is in crystalline form wherein the active agent is the same or different from the biological agent covalently bonded to the silane derivative moieties.
Preferred embodiments of the invention are described below with reference to the following accompanying drawings.
This disclosure of the invention is submitted in furtherance of the constitutional purposes of the U.S. Patent Laws “to promote the progress of science and useful arts” (Article 1, Section 8).
Medical implant devices are common in modern medicine in the treatment of a wide variety of conditions. However, implants can trigger biological problems and have side effects such as rejection of the device, allergic reaction and blood clot formation that can lead to thrombosis.
Modern implants include, for example, catheters, electrodes, stents, leads, pacemakers, cardioverter or defibrillator housings, artificial joints, screws, rods, ophthalmic implants, pins, bone plates, grafts, anastomotic devices, perivascular wraps, staples, shunts, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, vertebral disks, suture anchors, hemostatic barriers, clamps, plates, clips, vascular implants, tissue scaffolds, dressings, bone substitutes, intraluminal devices and vascular supports, to name but a few. In the case of stents and similar devices, the side effect of blood clot formation can lead to occlusion of the stent or the blood vessel in which it is inserted, and can even lead to death.
Described herein are implant devices and method of producing such devices, which have one or more bioactive agents covalently bound to the implant device to alleviate negative side effects.
As utilized herein, the term “bioactive agent” refers to a molecule that has biological activity. A bioactive agent can be synthetic or naturally occurring and includes but is not limited to biopolymers (peptides, proteins, nucleic acids), amino acids, pharmaceutical agents, and small organic molecules.
The term “compressed fluid” as used herein refers to a fluid of appreciable density (e.g. >2 g/cc) that is a gas at standard temperature and pressure. “Supercritical fluid”, “near critical fluid”, “near-supercritical fluid”, “critical fluid”, “densified fluid”, or “densified gas” as utilized herein refers to a compressed fluid under conditions wherein the temperature is at least 80% of the critical temperature of the fluid and the pressure is at least 50% of the critical pressure of the fluid.
Examples of substances that demonstrate supercritical or near critical behavior suitable for the present invention include, but are not limited to carbon dioxide, isobutylene, ammonia, water, methanol, ethanol, ethane, propane, butane, pentane, dimethyl ether, xenon, sulfur hexafluoride, halogenated and partially halogenated materials such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, perfluorocarbons (such as perfluoromethane and perfluoropropane, chloroform, trichloro-fluoromethane, dichloro-difluoromethane, dichloro-tetrafluoroethane) and mixtures thereof.
“Sintering” as used herein refers to the process by which parts of the matrix or the entire polymer matrix becomes continuous (e.g., formation of a continuous polymer film). As discussed below, the sintering process is controlled to produce a fully conformal continuous matrix (complete sintering) or to produce regions or domains of continuous coating while producing voids (discontinuities) in the matrix. The sintering process is controlled such that some phase separation is obtained between different polymers (e.g., polymers A and B) and/or to produce phase separation between discrete polymer particles. The adhesion properties of the coating are improved to reduce flaking or detachment of the coating from the substrate during manipulation in use through the sintering process. As described below, in some embodiments, the sintering process is controlled to provide incomplete sintering of the polymer matrix. In embodiments involving incomplete sintering, a polymer matrix is formed with continuous domains, and voids, gaps, cavities, pores, channels or interstices that provide spaces for sequestering therapeutic agents which can be released under controlled conditions. Depending on the nature of the polymer, the size of polymer particles and/or other polymer properties, a compressed gas, a densified gas, a near critical fluid or a super-critical fluid may be employed. In one example, carbon dioxide is used to treat a substrate that has been coated with a polymer and a drug, using dry powder and rapid expansion of supercritical solutions (RESS) electrostatic coating processes. In another example, isobutylene is employed in the sintering process. In other examples a mixture of carbon dioxide and isobutylene can be utilized.
When an amorphous material is heated to a temperature above its glass transition temperature, or when a crystalline material is heated to a temperature above a phase transition temperature, the molecules of the material are more mobile, which in turn means that they are more active and thus more prone to reaction such as oxidation. However, when an amorphous material is maintained at a temperature below its glass transition temperature, the amorphous molecules are substantially immobilized and thus less prone to reactions. Likewise, when a crystalline material is maintained at a temperature below its phase transition temperature, the crystalline molecules are substantially immobilized and thus less prone to reaction. Accordingly, processing drug components at mild conditions, such as the deposition and sintering conditions described herein, minimizes cross-reaction and degradation of the drug component. One type of reaction that is minimized by the processes of the invention relates to the ability to avoid conventional solvents which in turn minimizes auto-oxidation of the drug, whether in amorphous, semi-crystalline, or crystalline form, by reducing exposure thereof to free radicals, residual solvents and auto-oxidation initiators.
“Rapid Expansion of Supercritical Solutions” (RESS) as used herein involves the dissolution of a polymer into a compressed fluid, typically a supercritical fluid, followed by rapid expansion into a chamber at lower pressure, typically near atmospheric conditions. The rapid expansion of the supercritical fluid solution through a small opening, with its accompanying decrease in density, reduces the dissolution capacity of the fluid and results in the nucleation and growth of polymer particles. The atmosphere of the chamber is maintained in an electrically neutral state by maintaining an isolated “cloud” of gas in the chamber. Carbon dioxide or another appropriate gas employed to prevent electrical charge is transferred from the substrate to the surrounding environment.
“Bulk properties” of a coating that include a pharmaceutical or a biological agent which can be enhanced through the methods of the invention include for example: adhesion, smoothness, conformallity, thickness, and compositional mixing.
“Electrostatically charged”, “electrical potential” or “electrostatic capture” as used herein refers to the collection of the spray-produced particles upon a substrate that has a different electrostatic potential than the sprayed particles. Thus, the substrate is at an attractive electronic potential with respect to the particles exiting, which results in the capture of the particles upon the substrate (i.e. the substrate and particles are oppositely charged and the particles transport through the fluid medium of the capture vessel onto the surface of the substrate is enhanced via electrostatic attraction). This may be achieved by charging the particles and grounding the substrate or conversely charging the substrate and grounding the particles, or by some other process, which would be easily envisaged by one of skill in the art.
General aspects of the invention are illustrated and described with reference to
A layer 16 of silane material or alternative polymer material is disposed on surface 14. Layer 16 can be formed of a silane derivative that covalently bonds to surface 14 after oxidation of surface 14 (described below) or can be a polymer material having a silane derivative covalently bonded thereto through an organosilane linkage. The organosilane linkage can be either a dialkoxysilane silane or a monoalkoxysilane. The polymer can be either natural or synthetic. Natural polymers can include, for example cellulose, starch (amylase and amylopectin), proteins, silk, spider webs, polyhydroxyalkanoates, deoxyribonucleic acid (DNA), natural rubber and polysaccharides.
Where the substrate surface is stainless steel, the covalent attachment can be formed between oxidized Fe or oxidized Cr on surface 14 and Si of the silane material to form Fe—O—Si—R or Cr—O—Si—R. Covalent attachment of layer 16 to the implant substrate can advantageously inhibit or prevent loss of the layer, and any subsequently bound layers, during the life of the implant.
A layer 18 of bioactive agent is on and covalently attached to the silane material layer 16. The bioactive agent can be an agent targeted to alleviate the potential side effects of the particular implant device at issue. Where implant device 10 is a stent, layer 18 can comprise an antithrombogenic agent such as heparin. It is to be understood that layer 18 is not limited to a single bioactive agent and can comprise two or more bioactive agents simultaneously, each being covalently bound to the silane material.
Where the bioactive agent is a protein it can be preferable that the protein be bonded to the silane derivative of the silane material through a peptide bond. Accordingly, the silane derivative will be chosen to have appropriate exposed amino groups or carboxylic acid groups. When heparin is utilized as the bioactive agent, it can be preferable for the silane derivative to have terminal amino groups which form a peptide bond with a carboxyl group of the heparin molecule. Numerous silane derivatives having terminal amino groups are available for purposes of the present invention. One example of such a silane derivative is aminopropyltriethoxysilane (APTES). Alternatively, layer 16 can be formed of polymer material such as polyacrylamide, polyvinylamine, copolymers of polyacrylamide, polyvinyl amine and ethyleneimide, copolymers of isopropylacrylamide and polyvinylamine, copolymers of isopropylacrylamide and N-(3-aminopropyl)methacrylamide or other polymer or copolymer containing NH2 groups.
The thickness of layer 16 can vary and can be controlled by varying the reaction time and/or the silane concentration, as can the number of reactive NH2 sites. Accordingly, high coverage of bioactive agent can be achieved by increasing the number of active NH2 sites.
An alternative aspect of the invention is described with reference to
The form of PEG utilized is not limited to a particular derivative. Preferably, the PEG derivative is bifunctional, with a first reactive group on a first end for reacting with a surface group on the silane material. A second reactive group on the second end will preferably be capable of covalently bonding with the particular bioactive agent being utilized. Where the bioactive agent is heparin or another protein or peptide, the PEG derivative can preferably have a second reactive group comprising an amine group for forming a peptide bond with the bioactive agent. Where the silane derivative comprises terminal amine groups, it can be preferable that the PEG first reactive group comprises a reactive carboxyl group to form a peptide bond to the silane. Many such hetero-bifunctional PEG derivatives are available for use as linkers in the present application. Examples include but are not limited to COOH(CH2CH2O)nNH2, where n equals an integer.
The use of covalently bound active agents can increase the active life of the agent relative to non-covalently bound agents since the agent is unable to migrate away from the implant device where the activity is desired. Utilizing heparin as an example, when covalently bonded to a stent utilizing a silane material or silane/PEG linker, the active life of the heparin can be extended to up to 52 weeks or longer from the onset of activity (see below).
In an alternative aspect, the implant having the covalently bound bioactive agent can be coated as depicted in
It is to be understood that the bio-absorbable polymer layer can comprise mixtures of polymer materials and/or polymer and copolymer materials. For instance, the layer can contain at least two polymers and can comprise a first PLGA copolymer at a ratio of about 60:40 and a second PLGA copolymer at a ratio of from about 70:30 to about 90:10.
The bio-absorbable polymer layer is an over-coating relative to the underlying bioactive agent. Thus the polymer layer can delay the activity of the bioactive agent until some or all of the polymer material has been removed from the implant.
Referring next to
Example antistenotic drugs that can be utilized include but are not limited to paclitaxel and paclitaxel derivatives.
Example immunosuppressive drugs which can be utilized include but are not limited to macrolide immunosuppressive (limus) drugs selected from the group consisting of rapamycin (sirolimus), 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin, (2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin 4O—O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin, 4O—O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 4O—O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 4O—O-(2-Nicotinamidoethyl)-rapamycin4O—O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 4O—O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin, 4O—O-(2-Aminoethyl)-rapamycin, 4O—O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethylpapamycin, 42-Epi-(tetrazolyl)rapamycin(tacrolimus), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), including prodrugs, derivatives, analogs, hydrates and salt forms thereof.
The pharmaceutical agents can be within the layer of polymer as shown, or alternatively form a separate layer either beneath or over the polymer layer, or partially overlapping the polymer layer (not shown). In particular aspects the pharmaceutical agent can be held to the implant by physisorption. It can be preferable that at least 50% of the pharmaceutical be in crystalline form. The presence of the pharmaceutical in crystalline form can be confirmed by, for example, the x-ray spectrum, the Raman spectrum, the Differential Scanning Calorimetry (DSC) curve, the Wide Angle X-ray Scattering (WAXS) spectrum, the wide angle radiation scattering spectrum or the Infra Red (IR) spectrum.
Elution of the pharmaceutical agent into the body will occur over a period of time. It can be preferable that the pharmaceutical elution profile be such that about 10% to about 50% of at least one pharmaceutical agent elute within one week after implantation of the device (under physiological conditions). About 25% to about 75% of at least one pharmaceutical preferably elutes within two weeks and from about 50% to about 100% is eluted after about eight weeks. The amount and type of bio-absorbable polymer present can affect the elution profile of the pharmaceutical agent(s).
Referring to
In one particular embodiment where layer 20 is made up of multiple layers, layer 20 can comprise a first layer of bio-absorbable polymer, a second layer of pharmaceutical agent over the first layer, a third layer of bio-absorbable polymer over the second layer, a fourth layer of pharmaceutical agent over the third layer and an outer fifth layer of bio-absorbable polymer over the fourth layer. The first, third and fifth polymer layers can be the same or can differ, and the second and fourth pharmaceutical agent layers can be the same or can differ. In a specific example, the first, third and fifth polymer layers can comprise PLGA and the second and fourth pharmaceutical layers can comprise rapamycin.
The presence of layer 20, in any of the embodiments depicted in the figures, can serve as a coating and can temporarily inhibit or prevent activity of the underlying bioactive agent until enough of the bio-absorbable polymer has been absorbed to allow access to the bioactive agent. The coating can block the activity of the bioactive agent such that initiation of activity of the bioactive agent occurs after some time delay post implant. The delay of initiation of activity can be, for example, about three weeks.
Once the activity of the covalently bound bioactive agent occurs, the activity is sustained over a relatively long period of time as compared to non-covalently bound agent. In the case of heparin, the activity initiates approximately three weeks after implant (if a polymer coating is present) and is sustained at an effective level for at least 90 days. In particular applications, heparin's activity can be sustained for at least 120 days, 200 days or ever 52 weeks or longer.
The surface morphology of the implant can also play a role in both foreign body (negative) and healing (positive) responses. Nano-textured surfaces can be utilized for purposes of the present invention. These surfaces are created by including particles of IrO2, TiO2, SiO2 or hydroxyapatite and can be utilized to promote new tissue in a controlled positive manner. The underlying morphology/topology of the implant surface revealed after bio-absorption of the coating can be purposely designed to provide a clinical effect beyond that of a bare, smooth metal surface. These effects include promotion of cell adhesion and antithrombotic effects.
Methods of producing implants of the invention are described with reference to
Substrate 12 is treated with an acid or base to clean and oxidize surface 14, producing a hydroxylated surface as depicted in
After depositing silane layer 16, a desired bioactive agent 19 can be bonded to the available reactive amino groups of the silane layer as shown in
As shown in
The implant having covalently bound bioactive agent can be utilized as is or can be further coated as described below with reference to
Coating 20 can comprise at least one layer of bio-absorbable polymer. Example polymer materials are set forth above. A layer of bio-absorbable polymer material can be deposited utilizing a variety of methods. Preferred methods included but are not limited to Electrostatic Rapid Expansion of Supercritical Fluid Solutions (RESS), or Solution Enhanced Dispersion of Supercritical Fluids (SEDS). Alternative methods may include but are not limited to dip coating, vapor deposition and aerosol spray deposition.
Where RESS is utilized, the process can be as set forth in U.S. Pat. No. 6,756,084, issued to Fulton et al, hereby incorporated by reference herein. Utilizing the RESS process, densified gases in supercritical or liquid state are attractive media for the delivery of solid polymer material to be deposited in thin conformal films. Densified gas such as carbon dioxide or low molecular weight fluorinated hydrocarbons can be utilized as solvent. Rapid expansion of the solutions containing the dissolved solids from pressure or temperature conditions at which the solvents are in their supercritical fluid state through a small orifice or restrictor results in the formation of nanometer-scale solute particles suspended in a gaseous solvent stream.
To enhance RESS-generated nanoparticle collection efficiency on the surface of the implant, the RESS particles are charged during their formation utilizing an electric field applied to the tip of the expansion nozzle, or a secondary corona discharge in the presence of the nanoparticles, known as electrostatic RESS. Alternatively, the implant to be coated can be electrostatically charged to attract the nanoparticles in the RESS stream. The charged nanoparticles are thus attracted to the implant surface due to the electric field gradient, thus generating a uniform coating of polymer material. Due to the small size of the RESS particles, even implants having complex geometries, such as medical stents, can be coated uniformly and completely.
Once the RESS nanoparticles have been deposited, the newly formed layer is subjected to a sinter procedure to turn the RESS-deposited particles into a film. The sintering method utilized is based upon methodology disclosed in U.S. Pat. No. 6,794,902, issued to Yonker et al, incorporated by reference herein. In the sintering process, the particle-covered implant surface is contacted with a supercritical fluid under conditions sufficient for forming a continuous film from the polymer particles. The particles may have a particle size of less than or equal to about one micron. The method may be performed by providing a pressure vessel that can contain a compressible fluid. The implant having RESS-deposited particles is provided within the vessel and the compressible fluid is maintained at supercritical or sub-critical (but non-liquid) state sufficient for forming a film from the deposited polymer particles. The glass transition temperature (Tg) of the particles is reduced by subjecting the particles to the sintering conditions. This sintering method is advantageous in that thermally liable drugs and materials can be treated without loss of bioactivity.
SEDS can be utilized to form a layer of pharmaceutical. This method involves providing an aqueous solution of the pharmaceutical and decreasing the solvating power of the water by saturating it with carbon dioxide under supercritical conditions. The drug solution and a stream of supercritical carbon dioxide can be mixed utilizing a coaxial nozzle. The high velocity, turbulent, supercritical fluid stream breaks up the aqueous solution into very small droplets. A third stream containing an organic solvent can be utilized to overcome immiscibility problems between the aqueous and supercritical carbon dioxide phases. The three-nozzle process minimizes the amount of time that pharmaceuticals such as proteins, for instance, are exposed to denaturing conditions. Control over the size of the particle can be achieved by variation of process variables such as flow rates of the three input streams and pressure drop across the nozzle.
The drug coating can alternatively be applied by the electrostatic RESS process described above or by electrostatic deposition (eSTAT). Utilizing the eSTAT method, the pharmaceutical agent is micronized through milling, preserving the crystallinity of the agent. The micronized agent powder is dispersed into the coating system utilizing a pulse of CO2 gas. The finely dispersed drug powder is then electrostatically deposited on the implant substrate utilizing the same mechanism as electrostatic RESS.
The deposition methods described above allow controlled, micron thick layers of polymer or drug that can be deposited to form the layering patterns described above. Generating coatings and polymer films utilizing supercritical fluid technology circumvents the need to use and remove biologically detrimental organic solvents from coated biomaterials.
The release of pharmaceuticals into the host's body is controlled by the concentration of the agent, the layer thickness of the agent and the polymer and the kinetics of the sorption of the bio-absorbable polymer.
In compliance with the statute, the invention has been described in language more or less specific as to structural and methodical features. It is to be understood, however, that the invention is not limited to the specific features shown and described, since the means herein disclosed comprise preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims appropriately interpreted in accordance with the doctrine of equivalents.
This application claims priority under 35 U.S. C. §119 to U.S. Provisional Application Ser. No. 61/140,911 which was filed Dec. 26, 2008.
This invention was made with Government support under contract DE-AC0676RLO-1830, awarded by the U.S. Department of Energy. The Government has certain rights in this invention.
