CA2458828A1 - Optimized dosing for drug coated stents - Google Patents
Optimized dosing for drug coated stents Download PDFInfo
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- CA2458828A1 CA2458828A1 CA002458828A CA2458828A CA2458828A1 CA 2458828 A1 CA2458828 A1 CA 2458828A1 CA 002458828 A CA002458828 A CA 002458828A CA 2458828 A CA2458828 A CA 2458828A CA 2458828 A1 CA2458828 A1 CA 2458828A1
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- Prior art keywords
- paclitaxel
- stent
- drug
- coated
- micrograms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
The inventors have found that both the drug dose and drug release profiles are significant factors for the safety and efficacy of drug coated stents. The inventors have identified optimum dosing and release kinetics for drug coated stents. In particular, the inventors have determined dosing and release kinetics that permit the delivery of the lowest effective drug dosage, thus enhancing patient safety and minimizing any side effects from the drug.
Description
The present invention relates to optimized biological responses as a function of dosage and release kinetics of drugs from implantable medical devices.
BACKGROUND OF THE INVENTION
Stems are tubular scaffold structures used to prop open blood vessels and other body lumens. The most widespread use of stents is to open clogged coronary arteries and prevent restenosis. The use of stems coated with therapeutic agents has been proposed to help minimize the possibility of restenosis. For example, stems coated with paclitaxel have been shown to reduce restenosis rates when compared with uncoated stem s.
Although a number of drug coated stems have been reported, there has been a lack of published information regarding the optimization of drug dosing and drug release kinetics to address safety and efficacy. There is thus a need to identify, for a given coated stmt system, the effective therapeutic window based on the selection of an appropriate drug dose to obtain a desired biological response.
SUN~J'ARY OF THE INVENTION
The inventors have identified preferred drug dosing and drug release profiles for the safety and efficacy of drug coated stems. The embodiments described herein are specific to metallic stents_ coated with paclitaxel in a polymeric carrier, but the invention is thought to be applicable to stems coated with other drugs, with or without a polymeric carrier.
BACKGROUND OF THE INVENTION
Stems are tubular scaffold structures used to prop open blood vessels and other body lumens. The most widespread use of stents is to open clogged coronary arteries and prevent restenosis. The use of stems coated with therapeutic agents has been proposed to help minimize the possibility of restenosis. For example, stems coated with paclitaxel have been shown to reduce restenosis rates when compared with uncoated stem s.
Although a number of drug coated stems have been reported, there has been a lack of published information regarding the optimization of drug dosing and drug release kinetics to address safety and efficacy. There is thus a need to identify, for a given coated stmt system, the effective therapeutic window based on the selection of an appropriate drug dose to obtain a desired biological response.
SUN~J'ARY OF THE INVENTION
The inventors have identified preferred drug dosing and drug release profiles for the safety and efficacy of drug coated stems. The embodiments described herein are specific to metallic stents_ coated with paclitaxel in a polymeric carrier, but the invention is thought to be applicable to stems coated with other drugs, with or without a polymeric carrier.
In one embodiment, the invention includes a drug coated stmt comprising a structural member insertable into a body lumen of a patient, and a drug coated onto at least a portion of the said structural member. The drug is released from the stmt into the patient for a time period of at least eight days after insertion into the patient.
In another embodiment, the invention includes a drug coated stmt, where the drug i.s released from the stent at a varying rate over time. The rate is preferably maximized between one and three days after insertion into the patient.
In another embodiment, the invention includes a paclitaxel coated stmt wherein after ten days following insertion into a patient, only less than about 60 micrograms of paclitaxel is released from the stmt.
In another embodiment, the invention includes a paclitaxel coated stmt wherein after two days following insertion into a patient, only less than about 10 micrograms of paclitaxel is released from the stmt.
In another embodiment, the invention includes a paclitaxel coated stmt having a dosage of up to about 2 micrograms per square millimeter of the stmt surface area.
In yet another embodiment, the invention includes a paclitaxel coated stmt, wherein the paclitaxel is included in a polymer carrier and the weight fraction of the paclitaxel in the polymer carrier is less than about percent.
In another embodiment, the invention includes a drug coated stmt, where the drug i.s released from the stent at a varying rate over time. The rate is preferably maximized between one and three days after insertion into the patient.
In another embodiment, the invention includes a paclitaxel coated stmt wherein after ten days following insertion into a patient, only less than about 60 micrograms of paclitaxel is released from the stmt.
In another embodiment, the invention includes a paclitaxel coated stmt wherein after two days following insertion into a patient, only less than about 10 micrograms of paclitaxel is released from the stmt.
In another embodiment, the invention includes a paclitaxel coated stmt having a dosage of up to about 2 micrograms per square millimeter of the stmt surface area.
In yet another embodiment, the invention includes a paclitaxel coated stmt, wherein the paclitaxel is included in a polymer carrier and the weight fraction of the paclitaxel in the polymer carrier is less than about percent.
DESCRIPTION OF THE DRAWINGS
Figure l shows histology results from a porcine dosing study.
Figures 2a-2c illustrate the difference in biological response resulting from the difference in release rate from a paclitaxel coated stent.
DETATLED DESCRIPTION OF THE INVENTION
The inventors have found that both the drug dose and drug release profiles are significant factors for the safety and efficacy of drug coated stem s. The inventors have identified optimum dosing and release kinetics for drug coated stem s. In particular, the inventors have determined dosing and release kinetics that permit the delivery of the lowest effective drug dosage, thus enhancing patient safety and minimizing any side effects from the drug.
In a preferred embodiment of the present invention, the drug for coating a stmt is paclitaxel. Other drugs that may be useful for treating diseases such as restenosis include known anti-inflammatory, anti-thrombogenic, anti-angiogenic, matrix production inhibatory, anti-migratory, cytostatic, and/or cytotoxic agents. Drugs currently being used or considered as stmt coating materials to combat restenosis include paclitaxel, sirolimus, tacrolimus, and everolimus. The present invention is thought to be applicable to any of these restenosis inhibiting drugs.
In another preferred embodiment, the drug paclitaxel is contained in a polymer coating applied to a metallic scent. In certain embodiments, the polymer coating is a styrene-isobutylene based block copolymer, olefin polymer, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene copolymer, polyvinyl acetate, polystyrene, polyethylene teraphthalate), polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes,.. natural rubbers, polyester copolymers, styrene-butadiene copolymers ethylene vinyl acetate, polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polycaprolactone (PCL), poly-DL-lactic acid (DL-PLA) or poly-L-lactic acid (L-PLA), lactide, polyphosphazenes polyethylene oxide or polyethylene teraphtholate (PET), polybutylene teraphtholate (PBT), PEBAX, Nylon, or polycaprolactone, polyorthoesters, polylactic acids, polyglycolic acids, albumin or combinations of any of the above. In a most preferred embodiment, the polymer is a styrene-based polymer.
Paclitaxel coated metallic stems of various doses were implanted into healthy porcine arteries to determine the effect of dosage on biological response.
Dosages used were approximately 4.0, 2.0, 1.0, and 0.6 micrograms per square millimeter of the stmt surface area, corresponding to approximate total dosages of 345, 175, 85, and 50 micrograms per stmt. The paclitaxel was contained within a styrene-isobutylene based block copolymer applied to the stmt struts. As can be seen in Figure la, the highest dose (i.e. 4.0 micrograms/mm2) resulted in a pronounced vessel relaxation, fibrin accumulation, medial thinning, loss of endothelial cells, and possible thrombus formation.
As the dose is decreased, the adverse effects described for the 4.0 micrograms/mmz dose are minimized.
Figure l shows histology results from a porcine dosing study.
Figures 2a-2c illustrate the difference in biological response resulting from the difference in release rate from a paclitaxel coated stent.
DETATLED DESCRIPTION OF THE INVENTION
The inventors have found that both the drug dose and drug release profiles are significant factors for the safety and efficacy of drug coated stem s. The inventors have identified optimum dosing and release kinetics for drug coated stem s. In particular, the inventors have determined dosing and release kinetics that permit the delivery of the lowest effective drug dosage, thus enhancing patient safety and minimizing any side effects from the drug.
In a preferred embodiment of the present invention, the drug for coating a stmt is paclitaxel. Other drugs that may be useful for treating diseases such as restenosis include known anti-inflammatory, anti-thrombogenic, anti-angiogenic, matrix production inhibatory, anti-migratory, cytostatic, and/or cytotoxic agents. Drugs currently being used or considered as stmt coating materials to combat restenosis include paclitaxel, sirolimus, tacrolimus, and everolimus. The present invention is thought to be applicable to any of these restenosis inhibiting drugs.
In another preferred embodiment, the drug paclitaxel is contained in a polymer coating applied to a metallic scent. In certain embodiments, the polymer coating is a styrene-isobutylene based block copolymer, olefin polymer, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene copolymer, polyvinyl acetate, polystyrene, polyethylene teraphthalate), polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes,.. natural rubbers, polyester copolymers, styrene-butadiene copolymers ethylene vinyl acetate, polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polycaprolactone (PCL), poly-DL-lactic acid (DL-PLA) or poly-L-lactic acid (L-PLA), lactide, polyphosphazenes polyethylene oxide or polyethylene teraphtholate (PET), polybutylene teraphtholate (PBT), PEBAX, Nylon, or polycaprolactone, polyorthoesters, polylactic acids, polyglycolic acids, albumin or combinations of any of the above. In a most preferred embodiment, the polymer is a styrene-based polymer.
Paclitaxel coated metallic stems of various doses were implanted into healthy porcine arteries to determine the effect of dosage on biological response.
Dosages used were approximately 4.0, 2.0, 1.0, and 0.6 micrograms per square millimeter of the stmt surface area, corresponding to approximate total dosages of 345, 175, 85, and 50 micrograms per stmt. The paclitaxel was contained within a styrene-isobutylene based block copolymer applied to the stmt struts. As can be seen in Figure la, the highest dose (i.e. 4.0 micrograms/mm2) resulted in a pronounced vessel relaxation, fibrin accumulation, medial thinning, loss of endothelial cells, and possible thrombus formation.
As the dose is decreased, the adverse effects described for the 4.0 micrograms/mmz dose are minimized.
At 2.0, 1.0, and 0.6 micrograms/mm2, there is a corresponding decrease in the effects of paclitaxel, such that endothelial cell loss, medial thinning, fibrin accumulation, and possible thrombus formation are all 5 minimized. Based on these results, the preferred paclitaxel dosage is up to about 2.0 micrograms/mm2, more preferably less than about 1.5 micrograms/mm2, and most preferably up to about 1.0 micrograms/mm2.
In particular embodiments, the dosage is 0.4 to 2.0 micrograms/mm2, 0.7 to 1.5 micrograms/mm2, or 1.0 to 1.3 micrograms/mm2. In other embodiments, the dosage is 0.4, 0.5, 0..6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8; ~1.9, or 2.0 micrograms/mm2.
Using the 1.0 micrograms/mm2 dose as an exemplary embodiment, the effects of release rate were investigated. Metallic stems were coated with paclitaxel in a styrene-isobutylene based block copolymer carrier with the weight percent of paclitaxel in the carrier varying from approximately 8.8 'to about 35% . The dose of drug applied to the stems was kept at 1.0 micrograms/mm2, and the total drug dose was held constant by varying total coating weight. The results shown in Figure 2, as determined from in vitro release studies involving an aqueous environment, illustrate that the different weight fractions of paclitaxel in the polymer carrier resulted in different release kinetics.
In particular embodiments, the weight percent of paclitaxel in the carrier or polymer coating is 5o to 35%, 10a to 30%, 15% to 250, or 18% to 220.
As can be seen from Figure 2, there was a direct correlation between drug weight fraction in the carrier and the release rate. For example, the highest weight fraction tested (35%) resulted in the release. of approximately 45 micrograms of paclitaxel within two days after implantation. In contrast,.the lowest weight fraction tested (8.8%) resulted in the release of only about 2 micrograms of paclitaxel within the same time period. The fastest release rate (Figure 2a) resulted in noticeable fibrin accumulation, whereas slower rates (Figures 2b and 2c) did not result in this effect. It is thus demonstrated that drug release rate, in addition to drug dosing, affects biological response.
Based on these results, a high weight fraction of paclitaxel (35% in a polymer carrier) is acceptable, but a preferred weight fraction of paclitaxel is less than about 35o for a 1.0 micrograms/mmz dosage, more preferably up to about 25%.
Most preferably, dosing of approximately 1.0 micrograms/mmz of paclitaxel in a polymer coating was found to yield superior safety and efficacy. Within this dose, the preferred weight fraction of paclitaxel in this particular polymer carrier is less than about 35 0 . Such a combination results in the release of less than about 60 micrograms of paclitaxel within ten days after implantation, and less than about 45 micrograms within two days. As the inventors have found that lower doses lead to preferred physiologic responses, it is preferred that the coating sxstem result in the cumulative release of less than about 20 micrograms of paclitaxel ten days after implantation, more preferably less than 15 micrograms; more preferably less than 10 micrograms, more preferably less than 8 micrograms, more preferably less than 6 micrograms, and more preferably less than 4 micrograms. It is additionally preferred that less than 10 micrograms of paclitaxel be released two days after implantation, more preferably less than 5 micrograms, and more preferably less than 2 micrograms.
Figure 2 also demonstrates a continual release of drug over prolonged time frames. All curves in Figure 2 show a relatively rapid release rate over the first few days, followed by a slower, sustained release over up to about two weeks. The inventors have found that such release rate characteristics are preferred for efficacy.
In particular, the inventors have found that a coating system resulting in drug release for a period of at least eight days, and more preferably ten' days, is preferred. Also, the inventors have found that the period of rapid release rate is most effective if the maximum release rate is achieved during 1-3 days after implantation, more preferably during the second day after implantation.
Although most examples herein use a polymeric carrier to deliver paclitaxel from a coated stmt, it is anticipated that the optimal dosing and release rates identified by the inventors would apply to drug coated stmt systems in which no polymer carrier is used, such as where paclitaxel or another drug is applied directly to the stmt in the absence of a polymer carrier.
In ' still other embodiments, the stmt is a degradable polymer stmt that contains the paclitaxel, rather than being made from a biostable material that is coated with drug.
Although the invention is described as being specific to paclitaxel,, it should be recognized that the inventors' findings should be applicable to a wide variety of drug systems.
In particular embodiments, the dosage is 0.4 to 2.0 micrograms/mm2, 0.7 to 1.5 micrograms/mm2, or 1.0 to 1.3 micrograms/mm2. In other embodiments, the dosage is 0.4, 0.5, 0..6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8; ~1.9, or 2.0 micrograms/mm2.
Using the 1.0 micrograms/mm2 dose as an exemplary embodiment, the effects of release rate were investigated. Metallic stems were coated with paclitaxel in a styrene-isobutylene based block copolymer carrier with the weight percent of paclitaxel in the carrier varying from approximately 8.8 'to about 35% . The dose of drug applied to the stems was kept at 1.0 micrograms/mm2, and the total drug dose was held constant by varying total coating weight. The results shown in Figure 2, as determined from in vitro release studies involving an aqueous environment, illustrate that the different weight fractions of paclitaxel in the polymer carrier resulted in different release kinetics.
In particular embodiments, the weight percent of paclitaxel in the carrier or polymer coating is 5o to 35%, 10a to 30%, 15% to 250, or 18% to 220.
As can be seen from Figure 2, there was a direct correlation between drug weight fraction in the carrier and the release rate. For example, the highest weight fraction tested (35%) resulted in the release. of approximately 45 micrograms of paclitaxel within two days after implantation. In contrast,.the lowest weight fraction tested (8.8%) resulted in the release of only about 2 micrograms of paclitaxel within the same time period. The fastest release rate (Figure 2a) resulted in noticeable fibrin accumulation, whereas slower rates (Figures 2b and 2c) did not result in this effect. It is thus demonstrated that drug release rate, in addition to drug dosing, affects biological response.
Based on these results, a high weight fraction of paclitaxel (35% in a polymer carrier) is acceptable, but a preferred weight fraction of paclitaxel is less than about 35o for a 1.0 micrograms/mmz dosage, more preferably up to about 25%.
Most preferably, dosing of approximately 1.0 micrograms/mmz of paclitaxel in a polymer coating was found to yield superior safety and efficacy. Within this dose, the preferred weight fraction of paclitaxel in this particular polymer carrier is less than about 35 0 . Such a combination results in the release of less than about 60 micrograms of paclitaxel within ten days after implantation, and less than about 45 micrograms within two days. As the inventors have found that lower doses lead to preferred physiologic responses, it is preferred that the coating sxstem result in the cumulative release of less than about 20 micrograms of paclitaxel ten days after implantation, more preferably less than 15 micrograms; more preferably less than 10 micrograms, more preferably less than 8 micrograms, more preferably less than 6 micrograms, and more preferably less than 4 micrograms. It is additionally preferred that less than 10 micrograms of paclitaxel be released two days after implantation, more preferably less than 5 micrograms, and more preferably less than 2 micrograms.
Figure 2 also demonstrates a continual release of drug over prolonged time frames. All curves in Figure 2 show a relatively rapid release rate over the first few days, followed by a slower, sustained release over up to about two weeks. The inventors have found that such release rate characteristics are preferred for efficacy.
In particular, the inventors have found that a coating system resulting in drug release for a period of at least eight days, and more preferably ten' days, is preferred. Also, the inventors have found that the period of rapid release rate is most effective if the maximum release rate is achieved during 1-3 days after implantation, more preferably during the second day after implantation.
Although most examples herein use a polymeric carrier to deliver paclitaxel from a coated stmt, it is anticipated that the optimal dosing and release rates identified by the inventors would apply to drug coated stmt systems in which no polymer carrier is used, such as where paclitaxel or another drug is applied directly to the stmt in the absence of a polymer carrier.
In ' still other embodiments, the stmt is a degradable polymer stmt that contains the paclitaxel, rather than being made from a biostable material that is coated with drug.
Although the invention is described as being specific to paclitaxel,, it should be recognized that the inventors' findings should be applicable to a wide variety of drug systems.
Claims (29)
What is claimed is:
1. A drug coated stent comprising:
a structural member insertable into a body lumen of a patient; and a drug coated onto at least a portion of said structural member;
wherein said drug is released from said scent into the patient for a time period of at least eight days after insertion into the patient.
a structural member insertable into a body lumen of a patient; and a drug coated onto at least a portion of said structural member;
wherein said drug is released from said scent into the patient for a time period of at least eight days after insertion into the patient.
2. The drug coated stent of claim 1, wherein said drug is released from said scent into the patient for a time period of at least ten days after insertion into the patient.
3. The drug coated stent of claim 1, wherein said drug comprises paclitaxel.
4. The drug coated scent of claim 1, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
5. The drug coated stent of claim 4, wherein said polymer comprises styrene.
6. A drug coated scent comprising:
a structural member insertable into a body lumen of a patient; and a drug coated onto at least a portion of said structural member;
wherein said drug is released from said stent at a varying rate over time, said rate being maximized between one and three days after insertion into the patient.
a structural member insertable into a body lumen of a patient; and a drug coated onto at least a portion of said structural member;
wherein said drug is released from said stent at a varying rate over time, said rate being maximized between one and three days after insertion into the patient.
7. The drug coated stent of claim 6, wherein said rate is maximized at approximately two days after insertion into the patient.
8. The drug coated stent of claim 6, wherein said drug comprises paclitaxel.
9. The drug coated stent of claim 6, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
10. The drug coated stent of claim 9, wherein said polymer comprises styrene.
11. A paclitaxel coated stent comprising:
a structural member insertable into a body lumen of a patient; and paclitaxel coated onto at least a portion of said structural member;
wherein less than about 60 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
a structural member insertable into a body lumen of a patient; and paclitaxel coated onto at least a portion of said structural member;
wherein less than about 60 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
12. The paclitaxel coated stent of claim 11, wherein less than about 20 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
13. The paclitaxel coated stent of claim 11, wherein less than about 15 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
14. The paclitaxel coated stent of claim 11, wherein less than about 10 micrograms of paclitaxel is released from said scent ten days after exposure to an aqueous environment.
15. The paclitaxel coated stent of claim 11, wherein less than about 8 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
16. The paclitaxel coated stent of claim 11, wherein less than about 6 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
17. The paclitaxel coated stent of claim 11, wherein less than about 4 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
18. The paclitaxel coated stent of claim 11, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
19. The drug coated stent of claim 18, wherein said polymer comprises styrene.
20. A paclitaxel coated stent comprising:
a structural member insertable into a body lumen of a patient; and paclitaxel coated onto at least a portion of said structural member;
wherein less than about 10 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
a structural member insertable into a body lumen of a patient; and paclitaxel coated onto at least a portion of said structural member;
wherein less than about 10 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
21. The paclitaxel coated stent of claim 20, wherein less than about 5 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
22. The paclitaxel coated stent of claim 20, wherein less than about 2 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
23. A stent coated with paclitaxel, said paclitaxel having a dosage of up to about 2 micrograms per square millimeter of the stent surface area.
24. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area.
25. The stent of claim 23, wherein the paclitaxel is incorporated into a polymer carrier coated onto at least a portion of the stent.
26. The stent of claim 25, wherein. the polymer comprises styrene.
27. The stent of claim 23, wherein the weight fraction of the paclitaxel in the polymer carrier is less than about 35 percent.
28. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area, and the weight fraction of the paclitaxel in the polymer carrier is less than about 25 percent.
29. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area, and the weight fraction of the paclitaxel in the polymer carrier is less than about 8.8 percent.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US32409501P | 2001-09-24 | 2001-09-24 | |
US60/324,095 | 2001-09-24 | ||
PCT/US2002/030193 WO2003035135A1 (en) | 2001-09-24 | 2002-09-24 | Optimized dosing for drug coated stents |
Publications (1)
Publication Number | Publication Date |
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CA2458828A1 true CA2458828A1 (en) | 2003-05-01 |
Family
ID=23262051
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002458828A Abandoned CA2458828A1 (en) | 2001-09-24 | 2002-09-24 | Optimized dosing for drug coated stents |
Country Status (7)
Country | Link |
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US (2) | US6908622B2 (en) |
EP (1) | EP1429819B1 (en) |
JP (1) | JP4393870B2 (en) |
AU (1) | AU2002336764B2 (en) |
CA (1) | CA2458828A1 (en) |
DE (1) | DE60238422D1 (en) |
WO (1) | WO2003035135A1 (en) |
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- 2002-09-24 EP EP02773543A patent/EP1429819B1/en not_active Expired - Lifetime
- 2002-09-24 AU AU2002336764A patent/AU2002336764B2/en not_active Ceased
- 2002-09-24 DE DE60238422T patent/DE60238422D1/en not_active Expired - Lifetime
- 2002-09-24 WO PCT/US2002/030193 patent/WO2003035135A1/en active IP Right Grant
-
2005
- 2005-05-11 US US11/127,499 patent/US7906133B2/en active Active
Also Published As
Publication number | Publication date |
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WO2003035135A1 (en) | 2003-05-01 |
US20050202061A1 (en) | 2005-09-15 |
EP1429819A1 (en) | 2004-06-23 |
AU2002336764B2 (en) | 2007-03-29 |
US20030059454A1 (en) | 2003-03-27 |
US6908622B2 (en) | 2005-06-21 |
JP4393870B2 (en) | 2010-01-06 |
JP2005507002A (en) | 2005-03-10 |
EP1429819B1 (en) | 2010-11-24 |
US7906133B2 (en) | 2011-03-15 |
DE60238422D1 (en) | 2011-01-05 |
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FZDE | Discontinued |
Effective date: 20070924 |