Drug-eluting stent including crystalline cilostazol

Abstract

Provided is a stent comprising: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein elution of not more than 5% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate.

Claims

1. A stent comprising: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein the deposition layer has at least a first layer and a second layer; the content of cilostazol in the first layer, which is closer to the stent, is higher than the content of cilostazol in the second layer, which is more distant from the stent; and both layers comprise a bioabsorbable polymer, wherein elution of not more than 5% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate, and wherein a content of the crystalline cilostazol in the first layer is 55% by mass to 100% by mass.

2. A stent comprising: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein the deposition layer has at least a first layer and a second layer; the content of cilostazol in the first layer, which is closer to the stent, is higher than the content of cilostazol in the second layer, which is more distant from the stent; and both layers comprise a bioabsorbable polymer, wherein elution of not more than 20% by mass of the crystalline cilostazol occurs by 15 days after the stent is brought into contact in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate, and wherein a content of the crystalline cilostazol in the first layer is 55% by mass to 100% by mass.

3. The stent according to claim 1, wherein the bioabsorbable polymer comprises not less than 90% by mass of polylactic acid.

4. The stent according to claim 1, wherein the bioabsorbable polymer comprises L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and has a viscosity of 1.8 to 4.5 dL/g.

5. The stent according to claim 1, wherein the bioabsorbable polymer comprises not less than 90% by mass of L-lactide, and has a viscosity of 0.6 to 1.4 dL/g.

6. The stent according to claim 1, to be used for a peripheral blood vessel.

7. The stent according to claim 2, wherein the bioabsorbable polymer comprises not less than 90% by mass of polylactic acid.

8. The stent according to claim 2, wherein the bioabsorbable polymer comprises L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and has a viscosity of 1.8 to 4.5 dL/g.

9. The stent according to claim 2, wherein the bioabsorbable polymer comprises not less than 90% by mass of L-lactide, and has a viscosity of 0.6 to 1.4 dL/g.

10. The stent according to claim 2, to be used for a peripheral blood vessel.

11. The stent according to claim 1, wherein an outer and exposed layer is bioabsorbable.

12. The stent according to claim 11, wherein the first layer comprises 300 μg to 750 μg of cilostazol drug, and greater than 0 μg to 500 μg of the bioabsorbable polymer, and the second layer comprises 10 μg to 100 μg of cilostazol, and 180 μg to 540 μg of the bioabsorbable polymer.

13. The stent according to claim 2, wherein an outer and exposed layer is bioabsorbable.

14. The stent according to claim 11, wherein the bioabsorbable polymer comprises L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and has a viscosity of 1.8 to 4.5 dL/g, the first layer comprises 470±47 μg of cilostazol and 313±31 μg of the bioabsorbable polymer, and the second layer comprises 30±3 μg of cilostazol and 270±27 μg of the bioabsorbable polymer.

15. The stent according to claim 13, wherein the bioabsorbable polymer comprises L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and has a viscosity of 1.8 to 4.5 dL/g, the first layer comprises 470±47 μg of cilostazol and 313±31 μg of the bioabsorbable polymer, and the second layer comprises 30±3 μg of cilostazol and 270±27 μg of the bioabsorbable polymer.

16. The stent according to claim 1, wherein the second layer is an outer and exposed layer.

17. The stent according to claim 13, wherein the first layer comprises 300 μg to 750 μg of cilostazol drug, and greater than 0 μg to 500 μg of the bioabsorbable polymer, and the second layer comprises 10 μg to 100 μg of cilostazol, and 180 μg to 540 μg of the bioabsorbable polymer.

18. The stent according to claim 2, wherein the second layer is an outer and exposed layer.

19. The stent according to claim 1, wherein the bioabsorbable polymer comprising L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and having a viscosity of 1.8 to 4.5 dL/g, the first layer comprising 470±47 μg of cilostazol and 313±31 μg of the bioabsorbable polymer, the second layer comprising 30±3 μg of cilostazol and 270±27 μg of the bioabsorbable polymer.

20. The stent according to claim 2, wherein the bioabsorbable polymer comprising L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and having a viscosity of 1.8 to 4.5 dL/g, the first layer comprising 470±47 μg of cilostazol and 313±31 μg of the bioabsorbable polymer, the second layer comprising 30±3 μg of cilostazol and 270±27 μg of the bioabsorbable polymer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 schematically illustrates the whole shape (a) of a stent of an embodiment of the present invention, and a cross-section (b) of the stent along A-A.

(2) FIG. 2 schematically illustrates an embodiment of coating of a stent with a coating agent using an ultrasonic atomizer.

EMBODIMENT FOR CARRYING OUT THE INVENTION

(3) A stent of one embodiment of the present invention comprises: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer,
wherein elution of not more than 5% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate.

(4) A stent of another embodiment of the present invention comprises: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein elution of not more than 20% by mass of the crystalline cilostazol occurs by 15 days after the stent is brought into contact in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate.

(5) A stent of still another embodiment of the present invention comprises: a stent skeleton; a first layer deposited on the stent skeleton; and a second layer deposited on the first layer; the first layer and the second layer each comprising cilostazol and a bioabsorbable polymer, the bioabsorbable polymer comprising L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and having a viscosity of 1.8 to 4.5 dL/g, the first layer comprising 470±47 μg of cilostazol and 313±31 μg of the bioabsorbable polymer, the second layer comprising 30±3 μg of cilostazol and 270±27 μg of the bioabsorbable polymer.

(6) A stent of an embodiment of the present invention comprises: a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton.

(7) In an embodiment of the present invention, “stent skeleton” means a skeleton forming a stent, and is usually not limited as long as, for example, it is formed as a coarse-mesh cylinder using a metal or a polymer material, and as long as a desired stent of the present invention can be obtained therewith.

(8) Examples of the stent skeleton made of a metal include stent skeletons made of nickel, cobalt, chromium, titanium, or an appropriate alloy such as stainless steel. The stent skeleton is preferably a stent skeleton made of a metal comprising a cobalt-chromium alloy as a major component.

(9) A stent of an embodiment of the present invention comprises a deposition layer containing a plurality of layers deposited on the stent skeleton. Each layer of the deposition layer comprises crystalline cilostazol, and at least one of the plurality of layers comprises a bioabsorbable polymer.

(10) In the present description, “cilostazol” has the chemical name 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl. Cilostazol has platelet aggregation inhibition action, phosphodiesterase (PDE) inhibition action, antiulcer action, hypotensive action, and anti-inflammatory action, and is known to be useful as an antithrombotic drug, a cerebral circulation improver, an antiphlogistic, an antiulcer drug, an antihypertensive drug, an antiasthmatic drug, a phosphodiesterase inhibitor, and the like. The cilostazol is not limited as long as a desired stent of the present invention can be obtained therewith. The cilostazol also includes pharmaceutically acceptable salts thereof.

(11) The cilostazol is preferably crystalline. The cilostazol preferably has a crystal structure rather than having no crystal structure (rather than being amorphous), from the viewpoint of reducing the elution rate.

(12) In an embodiment of the present invention, the bioabsorbable polymer is not limited as long as a desired stent of the present invention can be obtained therewith. Examples of the bioabsorbable polymer include polylactic acid including lactide, and its molecular weight (Mw: weight average molecular weight) may be 40,000 to 700,000. Its viscosity may be 0.4 to 5.0 dL/g, or may be 0.4 to 4.2 dL/g. Further, the bioabsorbable polymer may comprise DL-lactide, L-lactide, or the like, and may comprise glycolide, caprolactone, or the like. Specific examples of the bioabsorbable polymer include: polymers containing DL-lactide having a molecular weight of 10,000 to 1,000,000; polymers containing L-lactide and DL-lactide at a mass ratio of 6:4 to 8:2, and having a molecular weight of 300,000 to 650,000 or a viscosity of 1.8 to 4.5 dL/g; and polymers having a molecular weight of 50,000 to 150,000 or containing not less than 90% by mass L-lactide, and having a viscosity of 0.6 to 1.4 dL/g (including poly(L-lactic acid) containing 100% by mass L-lactide). As the bioabsorbable polymer, a commercially available product may be used. Examples of the commercially available product include LR704S (trade name), L206S (trade name), and LR706S (trade name). The bioabsorbable polymers may be used either individually or in combination.

(13) The bioabsorbable polymer preferably comprises not less than 90% by mass, more preferably comprises not less than 93% by mass, still more preferably comprises 96% by mass polylactic acid. In cases where the bioabsorbable polymer comprises not less than 90% by mass polylactic acid, the polymer is capable of sustained release, which is an advantageous effect.

(14) The deposition layer has at least two layers, wherein the content of cilostazol in a first layer, which is closer to the stent skeleton, is preferably higher than the content of cilostazol in a second layer, which is more distant from the stent skeleton. In cases where the layer closer to the stent skeleton has a higher content of cilostazol, the layer allows sustained release for a long period, which is an advantageous effect.

(15) The content of cilostazol in the first layer is preferably 300 to 750 μg, more preferably 350 to 550 μg, still more preferably 440 to 480 μg. Further, the first layer preferably comprises 470±47 μg cilostazol.

(16) The content of cilostazol in the second layer is preferably 0 to 100 μg, more preferably 10 to 80 μg, still more preferably 20 to 60 μg. Further, the second layer preferably comprises 30±3 μg cilostazol.

(17) The content of cilostazol in the first layer is preferably 40 to 100% by mass, more preferably 50 to 70% by mass, still more preferably 55 to 65% by mass.

(18) The content of cilostazol in the second layer is preferably 0 to 50% by mass, more preferably 2 to 20% by mass, still more preferably 5 to 10% by mass.

(19) The deposition layer has at least two layers, wherein the content of cilostazol in a first layer, which is closer to the stent, is preferably higher than the content of cilostazol in a second layer, which is more distant from the stent, and wherein both layers preferably comprise a bioabsorbable polymer.

(20) The content of the bioabsorbable polymer in the first layer is preferably 0 to 500 μg, more preferably 250 to 350 μg, still more preferably 300 to 320 μg. Further, the first layer preferably comprises 313±31 μg of the bioabsorbable polymer.

(21) The content of the bioabsorbable polymer in the second layer is preferably 180 to 540 μg, more preferably 200 to 300 μg, still more preferably 260 to 285 μg. Further, the second layer preferably comprises 270±27 μg of the bioabsorbable polymer.

(22) The content of the bioabsorbable polymer in the first layer is preferably 0 to 60% by mass, more preferably 25 to 50% by mass, still more preferably 35 to 45% by mass.

(23) The content of the bioabsorbable polymer in the second layer is preferably not less than 70% by mass, more preferably not less than 80% by mass, still more preferably not less than 90% by mass.

(24) In a stent of an embodiment of the present invention, elution of not more than 3% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate.

(25) In a stent of an embodiment of the present invention, elution of not more than 20% by mass of the crystalline cilostazol preferably occurs by 15 days after the stent is brought into contact; elution of not more than 7% by mass of the crystalline cilostazol preferably occurs by 8 days after the stent is brought into contact; and elution of not more than 5% by mass, more preferably not more than 3% by mass, of the crystalline cilostazol preferably occurs by 1 day after the stent is brought into contact; in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate.

(26) In a stent of an embodiment of the present invention, elution of, for example, not less than 1.0% by mass of the crystalline cilostazol may occur, or not less than 0.1% by mass of the crystalline cilostazol may occur, by 15 days after the stent is brought into contact; elution of, for example, not less than 0.5% by mass of the crystalline cilostazol may occur, or not less than 0.05% by mass of the crystalline cilostazol may occur, by 8 days after the stent is brought into contact; elution of, for example, not less than 0.1% by mass of the crystalline cilostazol may occur, or not less than 0.01% by mass of the crystalline cilostazol may occur, by 1 day after the stent is brought into contact; in vitro at 37° C. with an elution medium of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate.

(27) In cases where elution of not more than the above-described ratio of the crystalline cilostazol occurs by the above-described time after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate, the cilostazol can be released for more than three months, so that the crystalline cilostazol can be allowed to be present in the living body for a very long time.

(28) Thus, a stent of an embodiment of the present invention can be suitably used, for example, for a peripheral blood vessel, preferably for a peripheral arterial blood vessel.

(29) Further, a stent of an embodiment of the present invention can also be used for, for example, relatively thick arteries for which stents have conventionally been used, such as heart coronary arteries and lower extremity arteries.

(30) As long as a desired stent of the present invention can be obtained, the method of producing a stent of an embodiment of the present invention is not limited.

(31) A stent of an embodiment of the present invention can be produced using, for example, a production method comprising: (i) providing a stent skeleton; (ii) providing a mixture containing cilostazol; (iii) coating the stent skeleton with the mixture; and repeating (ii) and (iii) (wherein the content of cilostazol, and/or the like is/are adjusted).

(32) The mixture containing cilostazol may contain the bioabsorbable polymer described above, in addition to the cilostazol. The mixture may also contain a solvent such as an additive. Since cilostazol is poorly soluble, the bioabsorbable polymer is required to prevent detachment of the coating, and to maintain high strength.

(33) The mixing mass ratio between the cilostazol and the bioabsorbable polymer such as polylactic acid is preferably 1:0.5 to 1:1.5. In cases where the ratio is within this range, a better intimal-thickening effect can be obtained. In cases where the mixing mass ratio is 1:1.1 to 1:1.5, the coating strength and the sustained-release effect can be further increased.

(34) In an embodiment of the present invention, the method of coating the stent skeleton with the mixture of cilostazol and the bioabsorbable polymer is not limited as long as a desired stent of the present invention can be obtained. For example, a simple spraying method, a dipping method, an electrodeposition method, an ultrasonic spray method, or the like that has been conventionally used may be employed. From the viewpoint of coating, it is preferred to use an ultrasonic spray method.

(35) The embodiments described above may be combined as appropriate when it is possible.

(36) Embodiments of the present invention are described below in detail with reference to drawings.

(37) FIG. 1(a) schematically illustrates a drug-eluting stent 1 of one embodiment of the present invention. The drug-eluting stent 1 has a cylindrical shape having a longitudinal axis, and a lumen is formed therein. In the drug-eluting stent 1, the cylindrical shape has a coarse-mesh-like side such that it is laterally expandable. Usually, the net may be formed with a member 2 (a wire of a metal or a polymer material) forming the stent skeleton. The drug-eluting stent 1 is usually inserted in an unexpanded form into the body. It is expanded at a treatment site in a blood vessel, and placed in the blood vessel. The expansion may be achieved by a balloon catheter in the blood vessel. FIG. 1(a) schematically illustrates the net. As long as a desired stent of the present invention can be obtained, the pattern of the net is not limited.

(38) FIG. 1(b) schematically illustrates a cross-section (A-A cross-section) of a wire forming the stent skeleton in FIG. 1(a).

(39) In a drug-eluting stent 1 of one embodiment of the present invention, a deposition layer 3 is formed on the stent skeleton member 2. The stent skeleton member 2 may be prepared using an arbitrary method. For example, it may be prepared by laser, electric discharge milling, chemical etching, or another means, from a hollow or formed stainless-steel tube. The stent skeleton member 2 may be formed with nickel, cobalt, chromium, titanium, or an appropriate alloy of stainless steel etc.

(40) The deposition layer 3 is formed with at least two layers. In FIG. 1(b), the plurality of layers are not illustrated.

(41) FIG. 2 schematically illustrates an ultrasonic spray coating device 4 for forming the deposition layer 3 by application on the stent skeleton member 2. Before the coating step, first, the surface of the stent skeleton member 2 is preferably subjected to plasma treatment using a plasma treatment apparatus (not shown). Thereafter, the stent skeleton member 2 is mounted on a mandrel, followed by attachment to the ultrasonic spray coating device 4. In the ultrasonic spray coating device 4, a coating liquid is transferred by a syringe pump through a pipe 6, and then atomized and sprayed by an ultrasonic spray nozzle 5. During the spray, the stent skeleton member 2 is linearly moved while rotating the member under the ultrasonic nozzle 5, to allow deposition of the deposition layer 3 on the stent skeleton member 2. Thereafter, while rotating and linearly moving the stent skeleton member 2, it is dried under nitrogen gas flow, followed by further drying it in a desiccator under reduced pressure. By this, a drug-eluting stent 1 can be prepared. Depending on the number of layers to be included in the deposition layer 3, different coating liquids are used to coat the stent skeleton member a plurality of times to form the deposition layer 3.

(42) Each coating liquid is provided using a mixture prepared by dissolving cilostazol and a bioabsorbable polymer in a solvent at a ratio in accordance with the deposition layer 3 to be formed. Since the deposition layer 3 includes a plurality of layers, a plurality of coating liquids need to be provided. As the coating solvent, a volatile solvent having a low boiling point may be used for enabling simple removal after coating. Examples of the volatile solvent include methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, isoamyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methylene chloride, chloroform, and dichloroethane; and mixed solvents containing at least two of these.

EXAMPLES

(43) The present invention is described below more concretely in more detail by way of Examples and Comparative Examples. However, these Examples are merely embodiments of the present invention, and the present invention is not limited by these examples at all.

(44) The polymers used in the present Examples are shown below in Table 1.

(45) TABLE-US-00001 TABLE 1 Molecular weight Composition (Mw: weight L: L-lactide average DL: DL-lactide Viscosity molecular G: glycoside Polymer (dL/g) weight) C: caprolactine (a) L206S 0.8-1.2 102,000   L = 100 (b) LR704S 2.0-2.8 >350,000 L:DL = 70:30 (c) LR706S 3.3-4.2 >630,000 L:DL = 70:30 (d) RG755S 0.50-0.70 63,000 DL:G = 75:25 (e) RG858S 1.3-1.7 220,000 DL:G = 85:15 (f) LC703S 1.3-1.8 257,000   L:C = 70:30

(46) The viscosity of each polymer described above means the limiting viscosity (ηη) (dL/g), which was measured by the capillary viscometer method. A sample solution with a concentration of C (g/dL) was provided, and the measured values of the flow time of the sample solution (t) and the flow time of the solvent (t0) were used to calculate the limiting viscosity according to the following equation.

(47) $\left[\eta \right]=\underset{C.fwdarw.︀0}{\lim }\frac{\ln \frac{t}{t_0}}{c}$

(48) An Ubbelohde viscometer was used as the apparatus, and chloroform (25° C.) was used as the solvent.

(49) Further, the weight average molecular weight (Mw) was determined using the Mark-Kuhn-Houwink equation (Mark-Howink-Sakurada equation).

EXAMPLE 1

(50) A cobalt-chromium alloy was used as the stent skeleton member 2. Cilostazol (CLZ) was dissolved in methylene chloride to provide a solution. By ultrasonic spray coating, this solution was applied to the base material cobalt-chromium alloy, to form a first layer composed of 440 μg of cilostazol.

(51) Subsequently, cilostazol and polymer (a) were mixed together at 1:9 (mass ratio), and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the first layer, to form a second layer composed of 540 μg of polymer (a) and 60 μg of cilostazol, to obtain a stent of Example 1.

EXAMPLES 2 AND 3

(52) Stents of Examples 2 and 3 were produced using the same method as the method described in Example 1 except that polymer (b) or polymer (c) was used instead of polymer (a).

COMPARATIVE EXAMPLES 1 TO 3

(53) Stents of Comparative Examples 1 to 3 were produced using the same method as the method described in Example 1 except that polymers (d) to (f) were used instead of polymer (a).

EXAMPLE 4

(54) A cobalt-chromium alloy was used as the stent skeleton member 2. Cilostazol and polymer (b) were mixed together at a ratio of 3:2, and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the cobalt-chromium alloy of the stent skeleton member, to form a first layer composed of 313 μg of polymer (b) and 470 μg of cilostazol.

(55) Subsequently, cilostazol and polymer (b) were mixed together at a ratio of 1:9 (mass ratio), and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the first layer, to form a second layer composed of 270 μg of polymer (b) and 30 μg of cilostazol, to obtain a stent of Example 4.

EXAMPLE 5

(56) A cobalt-chromium alloy was used as the stent skeleton member 2. Cilostazol and polymer (b) were mixed together at a ratio of 3:2, and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the base material cobalt-chromium alloy, to form a first layer composed of 323 μg of polymer (b) and 485 μg of cilostazol.

(57) Subsequently, cilostazol and polymer (b) were mixed together at a ratio of 1:19 (mass ratio), and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the first layer, to form a second layer composed of 285 μg of polymer (b) and 15 μg of cilostazol, to obtain a stent of Example 5.

EXAMPLE 6

(58) A cobalt-chromium alloy was used as the stent skeleton member 2. Cilostazol and polymer (b) were mixed together at a ratio of 3:2, and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the base material cobalt-chromium alloy, to form a first layer composed of 313 μg of polymer (b) and 470 μg of cilostazol.

(59) Subsequently, cilostazol and polymer (c) were mixed together at a ratio of 1:9 (mass ratio), and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the first layer, to form a second layer composed of 270 μg of polymer (c) and 30 μg of cilostazol, to obtain a stent of Example 6.

EXAMPLE 7

(60) A cobalt-chromium alloy was used as the stent skeleton member 2. Cilostazol and polymer (b) were mixed together at a ratio of 3:2, and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the base material cobalt-chromium alloy, to form a first layer composed of 490 μg of polymer (b) and 735 μg of cilostazol.

(61) Subsequently, cilostazol and polymer (b) were mixed together at a ratio of 1:19 (mass ratio), and dissolved in methylene chloride, to provide a solution. By ultrasonic spray coating, this solution was applied to the first layer, to form a second layer composed of 285 μg of polymer (b) and 15 μg of cilostazol, to obtain a stent of Example 7.

EXAMPLE 8

(62) Using the same method as the method described in Example 4 except that a first layer composed of 180 μg of polymer (b) and 270 μg of cilostazol was formed, a stent of Example 8 was obtained.

EXAMPLE 9

(63) Using the same method as the method described in Example 4 except that a first layer composed of 247 μg of polymer (b) and 370 μg of cilostazol was formed, a stent of Example 9 was obtained.

(64) Cilostazol Elution Test (In Vitro)

(65) 1. Method of Cilostazol Elution Test

(66) Using an elution tester 400-DS (Apparatus 7), and using 10 mL of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate as a test liquid, a test was carried out at an elution test liquid temperature of 37° C. with Dip Speed 10.

(67) Sampling was carried out 0.5, 1, 3, 6, 9, 12, 18, and 24 hours later. The whole amount of the test liquid was replaced at each collection time.

(68) 2. Measurement of Elution Rate of Cilostazol (HPLC Measurement)

(69) Under the following conditions, HPLC measurement was carried out for 10 μL of each sample solution or a standard solution. From the peak area values At and As of cilostazol, the elution rate was calculated.

(70) The elution rate was calculated using the following equation.

(71) TABLE-US-00002 $\left[Q\mathrm{hr}\left(\%\right)\right]=M_S\times \frac{{.Math.}_{i=P}^Q{A}_{\tau }i}{A_S}\times \frac{1}{C}\times A$ Q: Elution rate (% by mass) for the indicated amount of cilostazol at hour Q M.sub.S: Weighed amount of standard sample of cilostazol (mg) A.sub.T: Peak area of cilostazol sampled at hour i A.sub.S: Peak area of standard solution C: Indicated amount of cilostazol per stent (≈loaded amount of cilostazol) A: Constant (0.5) Σ.sub.i=P.sup.QA.sub.T.sup.i: Sum of the peak area of cilostazol from hour p to hour Q As the indicated amount of cilostazol per stent (C), the amount of loaded cilostazol calculated from the coating mass was used.
Measurement Conditions

(72) Detector: ultraviolet absorptiometer (measurement wavelength: 254 nm)

(73) Column: stainless-steel tube of 4.6 mm (inner diameter)×150 mm (length), packed with 5-μm octadecylsilyl-modified silica gel for liquid chromatography

(74) Column temperature: constant temperature near 25° C.

(75) Mobile phase: water/acetonitrile/methanol mixed liquid (10:7:3, v/v/v)

(76) Flow rate: adjusted such that the retention time of cilostazol was about 9 minutes

(77) Cilostazol Concentration in Arterial Tissue after Implantation in Rabbit Iliac Artery, and Residual Amount of Cilostazol on Stent (In Vivo)

(78) In a rabbit iliac artery, each of the stents of Examples and Comparative Examples was implanted. The implantation was carried out as follows.

(79) First, the neck of a rabbit is incised to expose the right carotid artery, and an introducer is placed therein. A balloon catheter guide wire is inserted from the introducer, and moved to the distal portion of the treatment site of the iliac artery under X-ray fluoroscopy. Thereafter, an angiographic catheter is inserted along the guide wire, and angiography is carried out for the treatment site of the iliac artery. After the completion of the angiography of the treatment site, a sample balloon catheter is inserted, along the balloon catheter guide wire, to the treatment site under X-ray fluoroscopy. After confirming that the sample stent (standard diameter: 2.75-mm stent diameter at an inflation pressure of 9 atm) is placed in the treatment site of the iliac artery (expected blood vessel diameter, 2.5 mm), the balloon is kept in an inflated state at 14 atm (hyperinflation; expected stent diameter, 3.0 mm; 20% by mass hyperinflation) using an indeflator for 20 seconds each time. After confirming expansion of the stent, the balloon is deflated, and the indeflator is removed, followed by pulling out the balloon catheter along the balloon catheter guide wire. The left and right iliac arteries are treated by the same method.

(80) Subsequently, the angiographic catheter is moved along the balloon catheter guide wire to a position before the treatment site, and angiography is carried out using a diluted contrast agent. After the left and right iliac arteries are treated by the same method, the angiographic catheter is pulled out. Finally, the blood vessel at the sheath insertion site is ligated, and the skin and the muscle layer are sutured. By the above process, the stent is placed in the iliac blood vessel of the rabbit.

(81) Ninety days after the implantation, the cilostazol concentration and the residual stent amount in the arterial tissue at the implantation site of each stent were analyzed.

(82) For pretreatment, the arterial tissue at the implantation site of each stent was separated from the stent. From each sample separated, an organic layer was obtained by liquid-liquid extraction, and then the organic layer was dried to provide a sample. The obtained sample was subjected to LC/MS/MS using the electrospray ionization method, to quantify cilostazol. The cilostazol concentration in the arterial tissue (μg cilostazol in 1 g of the tissue; μg/g tissue) and the residual amount of cilostazol (the residual ratio (%) of cilostazol on the stent) were calculated.

(83) Cilostazol Concentration in Arterial Tissue after Implantation in Pig Iliac Artery, and Residual Amount of Cilostazol on Stent (In Vivo)

(84) The cilostazol concentration in an arterial tissue after implantation in a pig iliac artery, and the residual amount of cilostazol, were evaluated using the same method as the method carried out for the rabbit, to analyze the cilostazol concentration in the arterial, tissue (μg cilostazol in 1 g of the tissue; μg/g tissue) and the residual amount of cilostazol (the residual ratio (%) of cilostazol on the stent) in a pig.

(85) TABLE-US-00003 TABLE 2 Example Comparative Example 1 2 3 1 2 3 First CLZ/polymer CLZ/polymer = CLZ/polymer = CLZ/polymer = CLZ/polymer = CLZ/polymer = CLZ/polymer = layer mass ratio 100/0 100/0 100/0 100/0 100/0 100/0 CLZ: μg CLZ: 400 CLZ: 400 CLZ: 400 CLZ: 400 CLZ: 400 CLZ: 400 Polymer: μg Polymer: 0 Polymer: 0 Polymer: 0 Polymer: 0 Polymer: 0 Polymer: 0 Second CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer layer mass ratio (a) = 1/9 (b) = 1/9 (c) = 1/9 (d) = 1/9 (e) = 1/9 (f) = 1/9 CLZ: μg CLZ: 60 CLZ: 60 CLZ: 60 CLZ: 60 CLZ: 60 CLZ: 60 Polymer: μg Polymer (a): Polymer (b): Polymer (c): Polymer (d): Polymer (e): Polymer (f): 540 540 540 540 540 540 Total CLZ: μg 500 500 500 500 500 500 CLZ 24 hours 1.7 3.2 1.1 51.7 17.3 39.6 elution rate (%)

(86) TABLE-US-00004 TABLE 3 Example 4 5 6 7 First layer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer mass ratio (b) = 3/2 (b) = 3/2 (b) = 3/2 (b) = 3/2 CLZ: μg CLZ: 470 CLZ: 485 CLZ: 470 CLZ: 735 Polymer: μg Polymer: 213 Polymer: 323 Polymer: 313 Polymer: 490 Second layer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer CLZ/polymer mass ratio (b) = 1/9 (b) = 1/19 (c) = 1/9 (b) = 1/19 CLZ: μg CLZ: 30 CLZ: 15 CLZ: 30 CLZ: 15 Polymer: μg Polymer (b): Polymer (b): Polymer (c): Polymer (b): 270 285 270 285 Total CLZ: μg 500 500 500 750 Rabbit CLZ 1 month later 100 96 88 100 residual ratio 3 months later 77 89 99.8 91 (%) Pig CLZ 3 months later 87 Not Not Not concentration 6 months later 57 measured measured measured in tissue.sup.a 9 months later 11 Pig CLZ 3 months later 70 Not Not Not residual ratio 6 months later 38 measured measured measured (%) 9 months later 2 CLZ elution 24 hours 1.6 Not Not Not rate (%) 96 hours 4.3 measured measured measured 15 days 13.2 .sup.aCilostazol (μg) in 1 g of tissue. Unit: μg/g tissue.

(87) TABLE-US-00005 TABLE 4 Example 8 9 First layer CLZ/polymer CLZ/polymer CLZ/polymer mass ratio (b) = 3/2 (b) = 3/2 CLZ: μg CLZ: 270 CLZ: 370 Polymer: μg Polymer: 180 Polymer: 247 Second layer CLZ/polymer CLZ/polymer CLZ/polymer mass ratio (b) = 1/9 (b) = 1/9 CLZ: μg CLZ: 30 CLZ: 30 Polymer: μg Polymer (b): Polymer (c): 270 270 Total CLZ: μg 300 400 Pig CLZ 3 months later 84 78 concentration 6 months later 46 36 in tissue.sup.a Pig CLZ 3 months later 66 60 residual ratio 6 months later 23 14 (%) CLZ elution 24 hours 1.7 2.7 rate (%) 96 hours 3.8 5.6 .sup.aCilostazol (μg) in 1 g of tissue. Unit: μg/g tissue.

(88) Each of the stents of Examples 1 to 9 comprises a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein elution of not more than 5% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate.

(89) Further, each of the stents of Examples 1 to 9 comprises a stent skeleton; and a deposition layer containing a plurality of layers deposited on the stent skeleton; each layer of the deposition layer comprising crystalline cilostazol, at least one of the plurality of layers comprising a bioabsorbable polymer, wherein elution of not more than 20% by mass of the crystalline cilostazol occurs by 15 days after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass of sodium lauryl sulfate.

(90) Thus, the stents of Examples 1 to 9 are capable of sustained release of cilostazol for more than three months.

(91) Needless to say, the plurality of layers applicable are not limited to two layers, and may be not less than three layers.

(92) In contrast, in each of the stents of Comparative Examples 1 to 3, elution of more than 5% by mass of the crystalline cilostazol occurs by 24 hours after the stent is brought into contact in vitro with an elution medium, at 37° C., of a phosphate-buffered sodium chloride solution containing 0.25% by mass sodium lauryl sulfate.

(93) Thus, the stents of Comparative Examples 1 to 3 are incapable of sustained release of cilostazol for more than three months.

INDUSTRIAL APPLICABILITY

(94) A drug-placing stent of an embodiment of the present invention is capable of allowing elution of not more than 5% by mass of crystalline cilostazol by 24 hours in a test on the elution rate in vitro. Alternatively or additionally, a drug-placing stent of an embodiment of the present invention is capable of allowing elution of not more than 20% by mass of crystalline cilostazol by 15 days in a test on the elution rate in vitro. Thus, the drug-placing stents of the embodiments of the present invention are capable of allowing elution of crystalline cilostazol for a longer period, and can be more suitably used for peripheral blood vessels.

RELATED APPLICATIONS

(95) The present application claims the priority under Article 4 of the Paris Convention based on the application of Application No. 2019-127529 filed in Japan on Jul. 9, 2019. The content of this priority application is incorporated in the present description by reference.

DESCRIPTION OF SYMBOLS

(96) 1. Stent 2. Stent skeleton member 3. Deposition layer 4. Ultrasonic spray coating device 5. Ultrasonic spray nozzle 6. Pipe