AU2007202976B2 - Optimized dosing for drug coated stents - Google Patents

Description

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AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant/s: Actual Inventor/s: Address for Service is: Boston Scientific Limited James J. Barry and Kalpana R. Kamath SHELSTON IP Margaret Street SYDNEY NSW 2000 CCN: 3710000352 Attorney Code: SW Telephone No: Facsimile No.

(02) 97771111 (02) 9241 4666 Invention Title: OPTIMIZED DOSING FOR DRUG COATED STENTS Details of Original Application No. 2002336764 dated 24 Sep 2002 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 41900AUP01 5012236341 .DOC/5844 00 OPTIMIZED DOSING FOR DRUG COATED STENTS c Related Application 0 The present application is a Divisional of Australian Patent Application No. AU 2002336764, the content of which is incorporated herein by reference.

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C Field of the Invention The present invention relates to optimised biological responses as a function of dosage and CI release kinetics of drugs from implantable medical devices.

Background of the Invention Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Stents 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 stents coated with therapeutic agents has been proposed to help minimise the possibility of restenosis. For example, stents coated with paclitaxel have been shown to reduce restenosis rates when compared with uncoated stents.

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

Although a number of drug coated stents have been reported, there has been a lack of published 00 information regarding the optimisation of drug dosing C1 and drug release kinetics to address safety and 0 efficacy. There is thus a need to identify, for a given coated stent system, the effective therapeutic 1 window based on the selection of an appropriate drug dose to obtain a desired biological response.

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C\ Summary of the Invention C< According to a first aspect of the present invention there is provided a drug coated stent, said C1 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 the drug is paclitaxel, and wherein the drug has a dosage of up to about 2 micrograms per square millimeter of the stent surface area.

Preferably, the drug has a dosage of between 0.4 micrograms and up to 2 micrograms per square millimeter of the stent surface area.

Preferably, the drug has a dosage of 1 microgram per square millimeter of the stent surface area.

Preferably, said drug has a total dosage of micrograms per stent.

Preferably, said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.

Preferably, said polymer carrier is a styreneisobutylene based block copolymer.

Preferably, the weight fraction of the drug in 00 the polymer carrier is between 8.8% and O According to another form of the present 0 invention there is provided 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 ri said structural member; wherein a drug release rate is maximised CI between one and three days after insertion into the patient.

Preferably, said drug release rate is maximised at approximately two days after insertion into the patient.

Preferably, said drug is released from said stent into the patient over a time period of at least eight days after insertion into the patient.

Preferably, said drug is released from said stent into the patient over a time period of at least ten days after insertion into the patient.

Preferably, up to about 60 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

Preferably, up to about 20 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

Preferably, up to about 15 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

Preferably, up to about 10 micrograms of drug has been released from said stent ten days after exposure 00 to an aqueous environment.

Preferably, up to about 8 micrograms of drug has O been released from said stent ten days after exposure to an aqueous environment.

5 Preferably, up to about 6 micrograms of drug has been released from said stent ten days after exposure

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IN to an aqueous environment.

C- Preferably, up to about 4 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

Preferably, less than about 10 micrograms of drug has been released from said stent two days after exposure to an aqueous environment.

Preferably, less than about 5 micrograms of drug has been released from said stent two days after exposure to an aqueous environment.

Preferably, less than about 2 micrograms of drug has been released from said stent two days after exposure to an aqueous environment.

Preferably, said drug has a dosage of 2 micrograms per square millimeter of the stent surface area.

Preferably, said drug has a total dosage of 175 micrograms per stent.

Preferably, said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.

Preferably, said polymer carrier is a styreneisobutylene based block copolymer.

The inventors have identified preferred drug dosing and drug release profiles for the safety and efficacy of drug coated stents. The embodiments described herein are specific to metallic stents 00 coated with paclitaxel in a polymeric carrier, but the Cl invention is thought to be applicable to stents coated O with other drugs, with or without a polymeric carrier.

0 In one embodiment, the invention includes a drug

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5 coated stent 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 C< drug is released from the stent into the patient for a C<1 time period of at least eight days after insertion into the patient.

CI In another embodiment, the invention includes a drug coated stent, where the drug is released from the stent at a varying rate over time. The rate is preferably maximised between one and three days after insertion into the patient.

In another embodiment, the invention includes a paclitaxel coated stent wherein after ten days following insertion into a patient, only less than about 60 micrograms of paclitaxel is released from the stent.

In another embodiment, the invention includes a paclitaxel coated stent wherein after two days following insertion into a patient, only less than about 10 micrograms of paclitaxel is released from the stent.

In another embodiment, the invention includes a paclitaxel coated stent having a dosage of up to about 2 micrograms per square millimeter of the stent surface area.

In yet another embodiment, the invention includes a paclitaxel coated stent, wherein the paclitaxel is included in a polymer carrier and the weight fraction of the paclitaxel in the polymer carrier is less than 00 0 about 35 percent.

0 Brief Description of the Drawings

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A preferred embodiment of the invention will now C 5 be described, by way of example only, with reference to the accompanying drawings in which:

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Figure 1 shows histology results from a porcine Cq dosing study.

C1 Figures 2a-2c illustrate the difference in r-.

C 10 biological response resulting from the difference in C1 release rate from a paclitaxel coated stent.

Detailed 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 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 minimising any side effects from the drug.

In a preferred embodiment of the present invention, the drug for coating a stent 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 stent coating materials to combat restenosis include paclitaxel, sirolimus, tacrolimus, and everolimus. The present invention is thought to 00 0 be applicable to any of these restenosis inhibiting Ci drugs.

O In another preferred embodiment, the drug paclitaxel is contained in a polymer coating applied CA 5 to a metallic stent. In certain embodiments, the polymer coating is a styrene-isobutylene based block

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copolymer, olefin polymer, polyethylene, C polypropylene, polyvinyl chloride, Cq polytetrafluoroethylene, fluorinated ethylene propylene copolymer, polyvinyl acetate, polystyrene, CA( poly(ethylene 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 stents 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 stent surface area, corresponding to approximate total dosages of 345, 175, 85, and 50 micrograms per stent. The paclitaxel was contained within a styrene-isobutylene based block copolymer applied to the stent struts. As can be seen in Figure la, the highest dose 00 0 micrograms/mm 2 resulted in a pronounced vessel C1 relaxation, fibrin accumulation, medial thinning, loss 0 of endothelial cells, and possible thrombus formation.

0 As the dose is decreased, the adverse effects C 5 described for the 4.0 micrograms/mm 2 dose are minimised. At 2.0, 1.0, and 0.6 micrograms/mm 2 there

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Sis a corresponding decrease in the effects of eCq paclitaxel, such that endothelial cell loss, medial CI thinning, fibrin accumulation, and possible thrombus r-.

formation are all minimised. Based on these results, CI the preferred paclitaxel dosage is up to about micrograms/mm 2 more preferably less than about micrograms/mm 2 and most preferably up to about micrograms/mm 2 In particular embodiments, the dosage is 0.4 to micrograms/mm 2 0.7 to 1.5 micrograms/mm 2 or to 1.3 micrograms/mm 2 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 micrograms/mm 2 Using the 1.0 micrograms/mm 2 dose as an exemplary embodiment, the effects of release rate were investigated. Metallic stents 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 stents was kept at 1.0 micrograms/mm 2 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 00 fractions of paclitaxel in the polymer carrier ri resulted in different release kinetics.

O In particular embodiments, the weight percent of paclitaxel in the carrier or polymer coating is 5% to 35%, 10% to 30%, 15% to 25%, or 18% to 22%.

As can be seen from Figure 2, there was a direct

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correlation between drug weight fraction in the carrier and the release rate. For example, the ri highest weight fraction tested resulted in the release of approximately 45 micrograms of paclitaxel ri within two days after implantation. In contrast, the lowest weight fraction tested 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 35% for a 1.0 micrograms/mm 2 dosage, more preferably up to about Most preferably, dosing of approximately micrograms/mm 2 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%. Such a combination results in the release of less than about 60 micrograms of paclitaxel within ten days after implantation, and less than about micrograms within two days. As the inventors have o00 C found that lower doses lead to preferred physiologic C1 responses, it is preferred that the coating system O result in the cumulative release of less than about 0 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 ri micrograms, and more preferably less than 4 ri micrograms. It is additionally preferred that less than 10 micrograms of paclitaxel be released two days ri after implantation, more preferably less than 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 stent, it is anticipated that the optimal dosing and release rates identified by the inventors would apply to drug coated stent systems in which no polymer carrier is used, such as where paclitaxel or another drug is 00 applied directly to the stent in the absence of a CI polymer carrier.

O In still other embodiments, the stent is a 0 degradable polymer stent that contains the paclitaxel, rather than being made from a biostable material that is coated with drug.

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Although the invention is described as being specific to paclitaxel, it should be recognised that CI the inventors' findings should be applicable to a wide variety of drug systems.

C1 Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

Although the invention has been described with reference to specific examples it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.

Claims (16)

1. A drug coated stent, said stent comprising: O a structural member insertable into a body lumen of a patient; and a drug coated onto at least a portion *D of said structural member, hwherein the drug is paclitaxel, and wherein the drug has a dosage of up to 10 about 2 micrograms per square millimeter of the stent surface area.

2. A stent according to claim 1, wherein the drug has a dosage of between 0.4 micrograms and up to 2 micrograms per square millimeter of the stent surface area.

3. A stent according to claim 1 or claim 2, wherein said drug has a dosage of 1 microgram per square millimeter of the stent surface area.

4. A stent according to claim 3, wherein said drug has a total dosage of 85 micrograms per stent. A stent according to claim 3, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.

6. A stent according to claim 5, wherein said polymer carrier is a styrene-isobutylene based block copolymer.

7. A stent according to claim 5 or claim 6, 00 wherein the weight fraction of the drug in the C- polymer carrier is between 8.8% and O 0 8. A stent according to any one of claims 3 to 7, C 5 wherein a drug release rate is maximised between one and three days after insertion into the patient. S9. A stent according to any one of claims 3 to 8, wherein said drug release rate is maximised at CI approximately two days after insertion into the patient. A stent according to any one of the preceding claims, wherein said drug is released from said stent into the patient over a time period of at least eight days after insertion into the patient.

11. A stent according to any one of the preceding claims, wherein said drug is released from said stent into the patient for a time period of at least ten days after insertion into the patient.

12. A stent according to any one of the preceding claims, wherein up to about 60 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

13. A stent according to any one of the preceding claims, wherein up to about 20 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment. 00 CI 14. A stent according to any one of the preceding O claims, wherein up to about 15 micrograms of 0 drug has been released from said stent ten days N 5 after exposure to an aqueous environment. \O A stent according to any one of the preceding C-I claims, wherein up to about 10 micrograms of C-I drug has been released from said stent ten days after exposure to an aqueous environment.

16. A stent according to any one of the preceding claims, wherein up to about 8 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

17. A stent according to any one of the preceding claims, wherein up to about 6 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

18. A stent according to any one of the preceding claims, wherein less than about 4 micrograms of drug has been released from said stent ten days after exposure to an aqueous environment.

19. A stent according to any one of the preceding claims, wherein less than about 10 micrograms of drug has been released from said stent two days after exposure to an aqueous environment. A stent according to any one of the preceding claims, wherein less than about 5 micrograms of drug has been released from said stent two days 00 after exposure to an aqueous environment. c( O 21. A stent according to any one of the preceding claims, wherein less than about 2 micrograms of 5 drug has been released from said stent two days after exposure to an aqueous environment. \O C-I 22. A stent according to any one of claims 1, 2 or C-I 8, wherein said drug has a dosage of 2 r-. micrograms per square millimeter of the stent C-I surface area.

23. A stent according to claim 22, wherein said drug has a total dosage of 175 micrograms per stent.

24. A stent according to claim 22 or claim 23, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member. A stent according to claim 24, wherein said polymer carrier is a styrene-isobutylene based block copolymer.

26. A drug coated stent, said stent substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings. Dated this 23rd day of October 2008 Shelston IP Attorneys for: Boston Scientific Limited