Patent Application
20090264975
The present invention relates to medical devices, and in particular, medical devices having a coating containing a therapeutic agent.
Many implantable medical devices are coated with drugs that are eluted from the medical device upon implantation. For example, some vascular stents are coated with a drug which is eluted from the stent for treatment of the vessel and/or to prevent some of the unwanted effects and complications of implanting the stent. In such drug-eluting medical devices, various methods have been proposed to provide a mechanism for drug elution. However, there is a continuing desire for improved devices and methods for providing drug elution from medical devices.
In one aspect, the present invention provides a medical device having a first configuration (e.g., unexpanded) and a second configuration (e.g., expanded), wherein the medical device comprises: (a) a reservoir containing a therapeutic agent; and (b) a barrier layer disposed over the reservoir, wherein the barrier layer comprises an inorganic material, wherein the barrier layer has a first permeability to the therapeutic agent when the medical device is in the first configuration and a second permeability to the therapeutic agent when the medical device is in the second configuration, and wherein the second permeability is greater than the first permeability.
In another aspect, the present invention provides a medical device comprising: (a) a reservoir containing a therapeutic agent; (b) a barrier layer disposed over the reservoir, wherein the barrier layer comprises an inorganic material; and (c) a swellable material disposed between the barrier layer and a surface of the medical device, wherein the swellable material is a material that swells upon exposure to an aqueous environment.
In yet another aspect, the present invention provides a medical device having a multi-layered coating, wherein the multi-layered coating comprises: (a) a first reservoir layer over a surface of the medical device, wherein the first reservoir layer comprises a first therapeutic agent; (b) a first barrier layer over the first reservoir layer, wherein the first barrier layer comprises a first inorganic material; (c) a second reservoir layer over the first barrier layer, wherein the second reservoir layer comprises a second therapeutic agent; (d) a second barrier layer over the second reservoir layer, wherein the second barrier layer comprises a second inorganic material; and (e) a plurality of excavated regions penetrating through at least a partial thickness of the multi-layered coating.
In yet another aspect, the present invention provides a medical device comprising: (a) a polymer layer comprising a block co-polymer, wherein the polymer layer contains a therapeutic agent; and (b) a barrier layer disposed over the polymer layer, wherein the barrier layer comprises an inorganic material, and wherein the barrier layer has a plurality of discontinuities.
The present invention also provides methods for forming a coating on medical devices and methods for delivering a therapeutic agent to a body site.
In one aspect, the present invention provides a medical device having a first configuration and a second configuration. The medical device comprises a reservoir containing a therapeutic agent. A barrier layer is disposed over the reservoir, wherein the barrier layer comprises an inorganic material.
Medical devices may have various types of first and second configurations. In some cases, the medical device is an expandable medical device having an unexpanded (first) configuration and an expanded (second) configuration. For example, the medical device may be an expandable stent or vascular graft which is delivered to the target body site in an unexpanded configuration and then expanded to the expanded configuration for implantation at the target site. Various other types of first/second configurations are also possible, including for example, unbent/bent configurations, unstretched/stretched configurations, or undeformed/deformed configurations.
The reservoir containing the therapeutic agent may be provided in various ways. The reservoir may be the therapeutic agent formulation alone, or may comprise any structure that retains or holds the therapeutic agent. For example, the reservoir may be a polymer layer or other layer over the medical device with the therapeutic agent disposed therein. In another example, the reservoir may be created in the surface of the medical device (e.g., a porous surface), or the medical device may have pits, pores, cavities, or holes that contain the therapeutic agent.
The barrier layer comprises an inorganic material, which may be selected on the basis of various considerations depending upon the particular application. For example, the inorganic material may be selected for its biologic properties (e.g., biocompatibility), structural properties (e.g., porosity), chemical properties (e.g., chemical reactivity), handling properties (e.g., storage stability), or the deposition techniques that can be used. Suitable inorganic materials for use in the barrier layer include inorganic elements, such as pure metals including aluminum, chromium, gold, hafnium, iridium, niobium, palladium, platinum, tantalum, titanium, tungsten, zirconium, and alloys of these metals (e.g., nitinol); and inorganic compounds, such as metal oxides (e.g., iridium oxide or titanium oxide), metal nitrides, and metal carbides, as well as inorganic silicides. Other suitable inorganic materials include certain carbon-containing materials that are traditionally considered inorganic materials, such as carbonized materials, carbon nanostructure materials, (e.g., carbon nanotubes, fullerenes, etc.), and diamond-like materials.
By being comprised of an inorganic material, the barrier layer may be useful in improving the biocompatibility or therapeutic effectiveness of the medical device. For example, the barrier layer may be useful in protecting body tissue from direct exposure to an underlying polymer layer that is less biocompatible than the barrier layer. Also, the barrier layer may present a more attractive surface for body tissue. For example, in the case of a vascular stent, the barrier layer may present a surface that promotes the migration and growth of endothelial cells, which can help to reduce the incidence of adverse effects related to stent implantation.
In some cases, the barrier layer may be formed using any of various layer deposition processes. For example, layer deposition processes that may be suitable for forming the barrier layer include: chemical vapor deposition, plasma vapor deposition, sputtering, pulsed laser deposition, sol-gel, evaporation (thermal, electron beam, etc.), molecular beam epitaxy, solution process (e.g., spray coating, dip coating, roll coating, etc.), or electrodeposition (e.g., electroplating, electrospray, etc.). The barrier layer may also be formed by carbonization (e.g., by laser heating or ion bombardment) of a precursor carbon material (e.g., a polymer) to form a barrier layer formed of an inorganic carbonized material.
The process used to form the barrier layer can be selected on the basis of various considerations, such as the type of medical device, the vulnerability of the therapeutic agent to heat degradation, or the type of inorganic material being used in the barrier layer. The thickness of the barrier layer will vary, depending upon the particular application. In some cases, the thickness of the barrier layer is in the range of 20 nm to 10 μm, but other thicknesses are also possible.
The barrier layer has a first permeability to the therapeutic agent when the medical device is in the first configuration and a second permeability to the therapeutic agent when the medical device is in the second configuration, with the second permeability being greater than the first permeability. Various possible degrees of permeability are possible for the first and second permeabilities of the barrier layer. In some cases, the first permeability does not provide a therapeutically effective release profile of the therapeutic agent (e.g., negligible or zero permeability), whereas the second permeability does provide a therapeutically effective release profile of the therapeutic agent. In some cases, the second permeability is at least 1.5-fold greater; and in some cases, at least 3.0-fold greater than the first permeability (where the first permeability is non-zero).
The second permeability is provided by discontinuities that are formed in the barrier layer when the medical device changes from the first configuration (e.g., unexpanded) to the second configuration (e.g., expanded). As used herein, the term “discontinuities” refers to discrete defects in the barrier layer that allow the passage of therapeutic agents through the barrier layer. Examples of such discrete defects include fractures lines, cracks, breaks, gaps, faults, holes, perforations, and other openings through the full thickness of the barrier layer. These discontinuities may have various dimensions and geometries, which can affect the permeability of the barrier layer. For example, wider discontinuities can increase the permeability of the barrier layer, and thus, increase the rate at which the therapeutic agent diffuses through the barrier layer. The discontinuities may be linear or curved, jagged or smooth, irregular or regular, or have any of various other patterns.
In addition to providing the second permeability, the discontinuities may also serve to relieve any stress on the adhesive bond between the barrier layer and the underlying substrate when the medical device undergoes deformation. By allowing the formation of discontinuities in the barrier layer, the barrier layer is made less sensitive to strain, thus relieving stress on the adhesive bond when the medical device undergoes deformation.
In certain embodiments, the medical device is provided in the first configuration (e.g., unexpanded) with the barrier layer having a plurality of regions of structural weakness. As used herein, “regions of structural weakness” refers to regions of relative weakness in the barrier layer such that when the barrier layer is strained, discontinuities will form and/or propagate in the regions of structural weakness. In certain embodiments, the regions of structural weakness are excavated regions in the barrier layer. As used herein, “excavated regions” refers to voids (e.g., holes, slots, grooves, channels, etchings, scribe lines, perforations, pits, etc.) that are created by removal of material using techniques that control the size, shape, and location of the voids. For example, such techniques include direct-write etching using energetic beams (e.g., laser, ion, or electron), micromachining, microdrilling, or lithographic processes.
The excavated regions may have various geometries and dimensions, which may be adjusted to achieve the desired amount of weakness in that particular region of the barrier layer. The excavated regions may extend partially or completely through the barrier layer. Increasing the depth of penetration of the excavated regions can increase the amount of weakness in that particular region of the barrier layer. In some cases, the excavated regions have an average penetration depth of 10%-90% through the thickness of the layer, but other average penetration depths are also possible. In some cases, the average penetration depth of the excavated regions is greater than 10% of the thickness of the barrier layer; and in some cases, greater than 33%; and in some cases, greater than 50%. Increasing the width of the excavated regions can also increase the amount of weakness in the barrier layer in that particular region. In some cases, the excavated regions have an average width in the range of 10 nm to 1 μm, but other average widths are also possible. The overall ratio between the surface area of the excavated regions and the non-excavated regions will vary depending upon the particular application. In some cases, the excavated regions may constitute 5-90%; and in some cases, 30-70% of the overall surface area, but other ratios are also possible Also, the surface area ratio of the excavated regions to the non-excavated regions may be different at different portions of the medical device.
For example, referring to the embodiment shown in
In operation, stent 10 is delivered to a body site in an unexpanded configuration. Once at the target body site, stent 10 is expanded. As shown in
The laser used in the etching process may be any of various lasers capable of ablating inorganic material, including excimer lasers. Various parameters, including for example, the wavelength, pulse energy, and/or pulse frequency of the laser, may be adjusted to achieve the desired result. The laser can be applied using direct-write techniques or by using masking techniques (e.g., laser lithography). In some cases, a cold ablation technique is used (e.g., using a femtosecond laser or a short wavelength excimer laser), which may be useful in reducing any damage to the therapeutic agent or, where a polymeric material is used in the medical device, in reducing damage to the polymeric material.
In certain embodiments, the excavated regions may extend through the full thickness of the barrier layer, with the excavated regions being filled with a biodegradable filler material. For example, referring to the embodiment shown in
In operation, the stent is delivered to a body site in an unexpanded state. Once at the target body site, the stent is expanded. As shown in
In certain embodiments, the regions of structural weakness are regions where the barrier layer has reduced thickness relative to the full thickness of the barrier layer. The regions of reduced thickness may be created in various ways during the formation of the barrier layer. In one example, the regions of reduced thickness may be created by disposing the barrier layer on a textured surface such that the barrier layer has reduced thickness in the regions that are located over the protruding features of the textured surface. The protruding features may be bumps, ridges, ribs, folds, corrugations, projections, prominences, elevations, or other features that protrude from the textured surface. The textured surface may form a pattern that is regular or irregular.
For example, referring to the embodiment shown in
In operation, the expandable stent is delivered to a body site in an unexpanded state. Once at the target body site, the expandable stent is expanded. As shown in
The regions of structural weakness may be distributed in various ways on different portions of the medical device. In certain embodiments, the regions of structural weakness are distributed uniformly throughout the medical device. In certain embodiments, the regions of structural weakness in the barrier layer at one portion of the medical device has different characteristics than those at a different portion of the medical device. In some cases, the regions of structural weakness are arranged and/or constructed to accommodate the location-dependent variation in strain forces that the barrier layer will experience when the medical device is changed from the first configuration to the second configuration. For example, in the expandable stent 10 of
For example, referring to the embodiment shown in
In another aspect, the present invention provides a medical device having a reservoir containing a therapeutic agent. Further, a barrier layer is disposed over the reservoir, wherein the barrier layer comprises an inorganic material. Further, a swellable material is disposed between the barrier layer and a surface of the medical device, wherein the swellable material is a material which swells upon exposure to an aqueous environment. Such swellable materials include water-swellable polymers and oxidizable metals. The composition and structure of the reservoir, as well as the manner in which it may be formed, are as described above. The composition and structure of the barrier layer, as well as the manner in which it may be formed, are as described above.
The barrier layer has a first permeability to the therapeutic agent prior to swelling of the swellable material and a second permeability to the therapeutic agent after swelling of the swellable material, with the second permeability being greater than the first permeability. In certain embodiments, the barrier layer may have regions of structural weakness as described above. When the swellable material swells, it applies outward pressure against the barrier layer. The strain imposed by this pressure causes the formation of discontinuities in the barrier layer, which increases the permeability of the barrier layer. Thus, the second permeability of the barrier layer is provided by discontinuities that form in the barrier layer upon swelling of the swellable material. Where the barrier layer has a plurality of regions of structural weakness, the discontinuities may form in these regions.
In certain embodiments, the swellable material is a water-swellable polymer that swells when it becomes hydrated. In such cases, the medical device is designed such that the water-swellable polymer becomes hydrated when the medical device is exposed to an aqueous environment (e.g., body fluid or tissue). The aqueous fluid may be distributed to the water-swellable polymer through various pathways. In certain embodiments, aqueous fluid has access to the water-swellable polymer via a pathway that does not involve the barrier layer. For example, aqueous fluid may have access to the water-swellable polymer through another portion of the medical device, or aqeuous fluid may be actively supplied to the water-swellable polymer by the medical device.
In certain embodiments, aqueous fluid from the external environment accesses the water-swellable polymer by passing through the barrier layer, which is allowed by a first, initial permeability of the barrier layer. This first, initial permeability of the barrier layer may be provided in various ways. In some cases, the barrier layer may be porous or semi-permeable. In some cases, the barrier layer may have one or more initially present discontinuities that allow the penetration of aqueous fluid through the barrier layer. These initially present discontinuities may be formed in various ways. One such method involves heating and/or cooling the barrier layer, which would cause thermal expansion and/or contraction of the barrier layer and result in the formation of discontinuities. For example, the barrier layer may be cooled by dipping the medical device into a cold solvent mixture or a cryogenic liquid (e.g., liquid nitrogen). In another example, the barrier layer may be subjected to alternating cycles of heating and cooling (or vice versa).
Any of a number of various types of water-swellable polymers known in the art may be used, including those that form hydrogels. Other examples of water-swellable polymers include polyethylene oxide, hydroxypropyl methylcellulose, poly(hydroxyalkyl methacrylate), polyvinyl alcohol, and polyacrylic acid. The water-swellable polymer may be applied to the medical device in various ways. For example, the water-swellable polymer may be provided in the form of gels, layers, fibers, agglomerates, blocks, granules, particles, capsules, or spheres. In some cases, the water-swellable polymer is contained within or underneath a polymer layer containing the therapeutic agent. In such cases, the polymer layer may serve to control the rate at which the water-swellable polymer becomes hydrated.
The following non-limiting examples further illustrate various embodiments of this aspect of the present invention. In one example, referring to the embodiment shown in
In operation, when the stent is delivered to a target body site, body fluid flows through pores 122 of barrier layer 120, diffuses through polymer layer 110, and hydrates the hydrogel in water-swellable layer 100. As shown in
In another example, referring to the embodiment shown in
In operation, when the stent is delivered to a target body site, body fluid flows through semi-permeable barrier layer 130, diffuses through polymer layer 114, and hydrates the hydrogel in capsules 102. As shown in
In another embodiment, the swellable material is an oxidizable metal that undergoes volume expansion upon oxidation (e.g., iron). The oxidation can occur upon exposure to an aqueous environment. As such, the oxidizable metal may be used in a manner similar to that for the water-swellable polymer described above.
In yet another aspect, the present invention provides a medical device having a multi-layered coating. The multi-layered coating comprises a first reservoir layer over a surface of the medical device, wherein the first reservoir layer comprises a first therapeutic agent. Further, a first barrier layer is disposed over the first reservoir layer, wherein the first barrier layer comprises a first inorganic material. Further, a second reservoir layer is disposed over the first barrier layer, wherein the second reservoir layer comprises a second therapeutic agent. The reservoir layers are formed using a material that is capable of retaining or holding the therapeutic agent, such as polymeric materials.
The first and second therapeutic agents may be the same or different. For example, one therapeutic agent may be an anti-thrombotic agent and the other therapeutic agent may be an anti-inflammatory agent to provide a combination treatment. Also, various characteristics of the first and second reservoir layers may be the same or different. Such characteristics include, for example, their composition, their density, their thicknesses, and the rate at which the therapeutic agents diffuse through the polymer layers. By independently controlling the characteristics of each reservoir layer, the release rate of the therapeutic agents can be adjusted.
Further, a second barrier layer is disposed over the second reservoir layer, wherein the second barrier layer comprises a second inorganic material. The composition and structure of the barrier layers, as well as the manner in which they may be formed, are as described above. Each barrier layer may each independently have their own various characteristics, including their composition, density, thickness, and permeability to the therapeutic agents.
Further, a plurality of excavated regions (as defined above) penetrate through at least a partial thickness of the multi-layered coating. The excavated regions provide a means by which therapeutic agents in the reservoir layers may be released into the external environment.
For example, referring to the embodiment shown in
The excavated regions may have various geometries and dimensions, including various sizes, widths, shapes, and degrees of penetration through the multi-layered coating. This feature may be useful in varying the release rate of the therapeutic agents. For example, referring to the embodiment shown in
In certain embodiments, the excavated regions on one portion of the medical device have different characteristics than the excavated regions on another portion of the medical device. These different characteristics can involve different geometries or dimensions, or a different arrangement (e.g., pattern, number, or density) of the excavated regions. This feature may be useful in providing different therapeutic agent release rates on different portions of the medical device, or the release of different therapeutic agents on different portions of the medical device. For example, a vascular stent may have larger or a higher density of excavated regions at the end portions of the stent than at the intermediate portions of the stent to reduce the unwanted “edge-effect” that sometimes occurs with stent implantation.
The first and second barrier layers may have varying degrees of permeability to the therapeutic agents, or be completely impermeable. In some cases, the first barrier layer and/or second barrier layer are impermeable so that the therapeutic agent is released only though the excavated regions in the multi-layered coating. The permeability of the barrier layers may be controlled in various ways, including selecting the thickness, the density, the deposition process used, and the composition of the barrier layers. By individually adjusting the permeability of the barrier layers, the release rate profiles of the therapeutic agents may be further controlled.
In certain embodiments, the multi-layered coating comprises a plurality of alternating reservoir layers and barrier layers. For example, there may be a third reservoir layer disposed over the second barrier layer, wherein the third reservoir layer comprises a third therapeutic agent; and a third barrier layer disposed over the third reservoir layer, wherein the third barrier layer comprises a third inorganic material.
In yet another aspect, the present invention provides a medical device having a polymer layer, which comprises a block copolymer and a therapeutic agent. Further, a barrier layer is disposed over the polymer layer. The barrier layer comprises an inorganic material and has a plurality of discontinuities. The composition and structure of the reservoir, as well as the manner in which it may be formed, are as described above. The composition and structure of the barrier layer, as well as the manner in which it may be formed, are as described above.
The inventors have discovered that depositing a thin layer of gold (by sputter deposition) onto a film of SIBS block copolymer on a stainless steel coupon unexpectedly resulted in the formation of nanometer-sized (about 20 nm wide) cracks in a reticulated pattern, as shown under 60,000-fold magnification in
Therefore, in this aspect of the present invention, the polymer layer (comprising a block copolymer) and the barrier layer have a synergistic relationship because the resulting formation of discontinuities in the barrier layer allows for the release of therapeutic agent in the polymer layer to the external environment. Also, the polymer layer and the barrier layer have an additional synergistic relationship because the resulting surface morphology of the barrier layer is believed to be capable of promoting endothelial cell attachment and/or growth, which may improve the therapeutic effectiveness of medical devices that are implanted in blood vessels.
In certain embodiments, the surface morphology of the polymer layer comprises a plurality of microphase-separated domains. In some cases, the surface morphology of the barrier layer follows the surface morphology of the polymer layer. In some cases, the discontinuities in the barrier layer follow the surface morphology of the polymer layer. Various characteristics of the microphase-separated domains (e.g., their size, geometry, and periodicity) on the surface of the polymer layer will depend upon the specific characteristics of the block copolymer, such as the relative chain lengths, positions, and composition of the blocks. As such, the block copolymer can be selected to achieve the desired surface morphology in the polymer layer, which in turn, will influence the formation of discontinuities and/or the surface morphology of the barrier layer.
In certain embodiments, the surface morphology of the barrier layer comprises a plurality of features elements or feature domains having a size that promotes endothelial cell attachment and/or growth. As used herein, the term “feature element” refers to any feature on a surface that causes the surface to be uneven, non-smooth, or discontinuous. For example, the feature elements may be bumps, nodules, ridges, grains, protrusions, pits, holes, openings, cracks, fracture lines, pores, grooves, channels, etc. As used herein, the term “feature domain” refers to a domain that is defined by one or more feature elements. For example, referring to schematic illustration of
In certain embodiments, the polymer layer is exposed to a solvent which dissolves the polymeric material in the polymer layer, but does not dissolve the therapeutic agent. In some cases, the solvent may access the polymer layer through the discontinuities in the barrier layer. For example, referring to the embodiment shown in
In an experimental example, a coating was formed by sputter-depositing a layer of gold onto an SIBS block copolymer film stainless steel coupon containing paclitaxel particles. This coating was then exposed to toluene, which penetrated through the cracks in the gold film and dissolved the SIBS polymer.
Non-limiting examples of medical devices that can be used with the present invention include stents, stent grafts, catheters, guide wires, neurovascular aneurysm coils, balloons, filters (e.g., vena cava filters), vascular grafts, intraluminal paving systems, pacemakers, electrodes, leads, defibrillators, joint and bone implants, spinal implants, access ports, intra-aortic balloon pumps, heart valves, sutures, artificial hearts, neurological stimulators, cochlear implants, retinal implants, and other devices that can be used in connection with therapeutic coatings. Such medical devices are implanted or otherwise used in body structures, cavities, or lumens such as the vasculature, gastrointestinal tract, abdomen, peritoneum, airways, esophagus, trachea, colon, rectum, biliary tract, urinary tract, prostate, brain, spine, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and the like.
The therapeutic agent used in the present invention may be any pharmaceutically acceptable agent such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaparin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof, antibiotics such as gentamycin, rifampin, minocyclin, and ciprofloxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; angiotensin converting enzyme (ACE) inhibitors; beta-blockers; βAR kinase (βARK) inhibitors; phospholamban inhibitors; protein-bound particle drugs such as ABRAXANE™; structural protein (e.g., collagen) cross-link breakers such as alagebrium (ALT-711); any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include serca-2 protein, monocyte chemoattractant proteins (MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factors α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin-like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase and combinations thereof and other agents useful for interfering with cell proliferation.
Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin−) cells including Lin-CD34−, Lin−CD34+, Lin−cKit+, mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts+5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells. Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
The polymeric materials used in the present invention may comprise polymers that are biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polystyrene; polystyrene maleic anhydride; block copolymers such as styrene-isobutylene-styrene block copolymers (SIBS) and styrene-ethylene/butylene-styrene (SEBS) block copolymers; polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides including poly(methylmethacrylate-butylacetate-methylmethacrylate) block copolymers; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polyurethanes; polycarbonates, silicones; siloxane polymers; cellulosic polymers such as cellulose acetate; polymer dispersions such as polyurethane dispersions (BAYHYDROL®); squalene emulsions; and mixtures and copolymers of any of the foregoing.
Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butyl acrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and acrylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose, and hydroxypropyl methyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the foregoing. The biodegradable polymer may also be a surface erodable polymer such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc calcium phosphate.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art and such modifications are within the scope of the present invention.
The present application claims priority to U.S. provisional application Ser. No. 61/047,002 filed Apr. 22, 2008, the disclosure of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61047002 | Apr 2008 | US |
