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Kafe 바로가기국가/구분 | United States(US) Patent 등록 |
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국제특허분류(IPC7판) |
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출원번호 | UP-0975174 (2004-10-28) |
등록번호 | US-7517362 (2009-07-01) |
발명자 / 주소 |
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출원인 / 주소 |
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인용정보 | 피인용 횟수 : 5 인용 특허 : 324 |
The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer t
The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer that allows for controlled release of the therapeutic agents.
What is claimed is: 1. An implantable medical device comprising: an implantable device body having a plurality of holes; a therapeutic agent provided in a first therapeutic agent layer and contained within the plurality of holes in the device body; and at least one mixing layer provided adjacent th
What is claimed is: 1. An implantable medical device comprising: an implantable device body having a plurality of holes; a therapeutic agent provided in a first therapeutic agent layer and contained within the plurality of holes in the device body; and at least one mixing layer provided adjacent the first therapeutic agent layer in the plurality of holes; wherein the therapeutic agent layer and the at least one mixing layer together contain a continuous concentration gradient of said therapeutic agent and allow for the controlled release of the therapeutic agent contained within the therapeutic agent layer and the at least one mixing layer. 2. The implantable medical device of claim 1, wherein the at least one mixing layer is a pharmaceutically acceptable bioresorbable matrix that allows the therapeutic agent contained within the therapeutic agent layer and the at least one mixing layer to be released as the matrix resorbs. 3. The implantable medical device of claim 2, wherein said pharmaceutically acceptable bioresorbable matrix comprises at least one pharmaceutically acceptable polymer. 4. The implantable medical device of claim 3, wherein said pharmaceutically acceptable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, lipids, and mixtures thereof. 5. The implantable medical device of claim 4, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as a solid solution in said at least one mixing layer. 6. The implantable medical device of claim 4, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said at least one mixing layer. 7. The implantable medical device of claim 4, wherein said therapeutic agent from the therapeutic agent layer is heterogeneously disposed in said at least one mixing layer. 8. The implantable medical device of claim 7, wherein said therapeutic agent from the therapeutic agent layer is homogeneously or heterogeneously disposed in said at least one mixing layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent. 9. The implantable medical device of claim 1, wherein the therapeutic agent layer comprises the therapeutic agent and a water soluble binding agent. 10. The implantable medical device of claim 9, wherein the binding agent is a pharmaceutically acceptable polymer selected from the group consisting of poly ethylene glycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polysaccharides, polysaccharide derivatives, poly hyaluronic acid, poly alginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid, and proteins. 11. The implantable medical device of claim 9, wherein the at least one mixing layer includes a polymer different from the water soluble binding agent 12. The implantable medical device of claim 11, wherein the at least one mixing layer includes a plurality of mixing layers formed by a process comprising: sequentially delivering a substantially identical composition to the implantable medical device for each of the layers which take on the concentration gradient into the plurality of holes. 13. The implantable medical device of claim 1, wherein the at least one mixing layer is formed by a process comprising: delivering a polymer without the therapeutic agent to the holes; and liquefying a portion of the therapeutic agent layer with said polymer, the at least one mixing layer acquiring therapeutic agent from the therapeutic agent layer. 14. The implantable medical device of claim 9, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer. 15. The implantable medical device of claim 9, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer. 16. The implantable medical device of claim 9, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer. 17. The implantable medical device of claim 9, wherein said therapeutic agent is homogeneously or heterogeneously disposed in said therapeutic agent layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent. 18. The implantable medical device of claim 1, wherein the therapeutic agent is selected from the group consisting of antithrombotic agents, antineoplastic agents, neoplastic agents, antiproliferative agents, antisense compounds, immunosuppresants, angiogenic agents, angiogenic factors, antiangiogenic agents, and anti-inflammatory agents, or combinations thereof. 19. The implantable medical device of claim 1, wherein the therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide. 20. The implantable medical device of claim 1, wherein said therapeutic agent is an agent selected for treatment of restenosis or inflammation. 21. The implantable medical device of claim 1, wherein the implantable medical device is a stent. 22. An implantable medical device comprising: an implantable device body having a plurality of holes; a therapeutic agent within the plurality of holes in the device body provided in a therapeutic agent layer; and a mixing layer provided in the plurality of holes; wherein the therapeutic agent layer and the mixing layer contain a continuous concentration gradient of said therapeutic agent created by a process comprising delivering a mixing layer material without the therapeutic agent, and liquefying a portion of the therapeutic agent layer with the mixing layer material, wherein the mixing layer has a smaller amount of therapeutic agent contained therein than the therapeutic agent layer. 23. The implantable medical device of claim 22, wherein the mixing layer is a pharmaceutically acceptable bioresorbable matrix that allows the therapeutic agent contained within the therapeutic agent layer and the mixing layer to be released as the matrix resorbs. 24. The implantable medical device of claim 23, wherein said bioresorbable matrix comprises at least one pharmaceutically acceptable polymer. 25. The implantable medical device of claim 24, wherein said pharmaceutically acceptable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, lipids, and mixtures thereof. 26. The implantable medical device of claim 24, wherein the therapeutic agent layer comprises at least one pharmaceutically acceptable polymer different from the pharmaceutically acceptable polymer of the mixing layer. 27. The implantable medical device of claim 22, wherein the therapeutic agent layer comprises the therapeutic agent and a water soluble binding agent. 28. The implantable medical device of claim 27, wherein the binding agent is a pharmaceutically acceptable polymer selected from the group consisting of poly ethylene glycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polysaccharides, polysaccharide derivatives, poly hyaluronic acid, poly alginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid, and proteins. 29. The implantable medical device of claim 27, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer. 30. The implantable medical device of claim 27, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer. 31. The implantable medical device of claim 27, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer. 32. The implantable medical device of claim 31, wherein said therapeutic agent is homogeneously or heterogeneously disposed in said therapeutic agent layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent. 33. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as a solid solution in said mixing layer. 34. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as multi-phase mixture in said mixing layer. 35. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is heterogeneously disposed in said mixing layer. 36. The implantable medical device of claim 35, wherein said therapeutic agent from the therapeutic agent layer is homogeneously or heterogeneously disposed in said mixing layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent. 37. The implantable medical device of claim 22, wherein the therapeutic agent is selected from the group consisting of antithrombotic agents, antineoplastic agents, neoplastic agents, antiproliferative agents, antisense compounds, immunosuppresants, angiogenic agents, angiogenic factors, antiangiogenic agents, and anti-inflammatory agents, or combinations thereof. 38. The implantable medical device of claim 22, wherein the therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide. 39. The implantable medical device of claim 22, wherein said therapeutic agent is an agent selected for treatment of restenosis or inflammation. 40. The implantable medical device of claim 22, wherein the implantable medical device is a stent. 41. A method for preparing an implantable medical device, which method comprises: a) providing an implantable medical device with a plurality of holes; b) loading into the plurality of holes an amount of a liquefied therapeutic agent, which amount is sufficient to form a therapeutic agent layer; c) allowing said liquefied therapeutic agent layer to at least partially solidify; d) loading into the plurality of holes an amount of a liquefied bioresorbable polymer which amount is sufficient to liquefy a portion of the therapeutic agent layer, thereby causing a portion of the therapeutic agent to be disposed within a mixing layer; e) allowing said liquefied bioresorbable polymer and said portion of the therapeutic agent layer to solidify; wherein an amount of therapeutic agent contained within the mixing layer upon solidification is smaller than an amount of therapeutic agent contained in the therapeutic agent layer; and further wherein steps d and e may optionally be repeated to form multiple mixing layers. 42. The method for preparing an implantable medical device of claim 41, comprising: liquefying the therapeutic agent by maintaining the therapeutic agent at a temperature that is higher than its melting point, or glass transition temperature. 43. The method for preparing an implantable medical device of claim 41, comprising: forming the liquefied therapeutic agent by dissolving the therapeutic agent in a solvent. 44. The method for preparing an implantable medical device of claim 41, comprising: liquefying the bioresorbable polymer by maintaining the bioresorbable polymer at a temperature that is higher than its melting point, or glass transition temperature. 45. The method for preparing an implantable medical device of claim 41, comprising: forming the liquefied bioresorbable polymer by dissolving the bioresorbable polymer in a solvent. 46. The method for preparing an implantable medical device of claim 41, further comprising: forming a barrier layer by loading into the plurality of holes an amount of a liquefied biocompatible polymer, which amount is sufficient to form a barrier layer, wherein said loading is performed so that the barrier layer is located adjacent the therapeutic agent layer. 47. The method for preparing an implantable medical device of claim 46, comprising: liquefying the biocompatible polymer by maintaining the biocompatible polymer at a temperature that is higher than its melting point, or glass transition temperature. 48. The method for preparing an implantable medical device of claim 46, comprising: forming the liquefied biocompatible polymer by dissolving the biocompatible polymer in a solvent. 49. The method for preparing an implantable medical device of claim 41, wherein loading the liquefied bioresorbable polymer into the holes comprises loading liquefied bioresorbable polymer which does not contain the therapeutic agent. 50. The method for preparing an implantable medical device of claim 41, wherein the liquefied therapeutic agent layer comprises the therapeutic agent and a pharmaceutically acceptable polymer. 51. The method for preparing an implantable medical device of claim 50, wherein the liquefied therapeutic agent layer comprises from about 50% to about 95% therapeutic agent and from about 5% to about 50% pharmaceutically acceptable polymer. 52. The method for preparing an implantable medical device of claim 41, wherein loading of the liquefied therapeutic agent and the liquefied bioresorbable polymer comprises dropwise loading. 53. The method for preparing an implantable medical device of claim 41, wherein loading of the liquefied therapeutic agent and the liquefied bioresorbable polymer comprises loading with a piezoelectric micro-jetting device. 54. An implantable medical device comprising: an implantable device body having a plurality of through holes; a plurality of layers of a bioresorbable polymer formed in the through holes to form a barrier layer at a first side of the holes; a plurality of layers of a bioresorbable polymer and drug formed in the through holes to form a drug layer adjacent the barrier layer; a plurality of layers of a bioresorbable polymer formed in the through holes to form a cap layer at a second side of the holes; and wherein the drug layer and the cap layer mix to form a continuous concentration gradient. 55. The implantable medical device of claim 54, wherein the drug layer comprises 2-chlorodeosyadenosine. 56. The implantable medical device of claim 54, wherein the drug layer comprises paclitaxel. 57. The implantable medical device of claim 54, wherein the drug layer comprises rapamycin. 58. The implantable medical device of claim 54, wherein the barrier layer bioresorbable polymer and the drug layer bioresorbable polymer are different. 59. The implantable medical device of claim 54, wherein the barrier layer bioresorbable polymer and the cap layer bioresorbable polymer are the same.
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