Drug-eluting stent

Abstract

A drug-eluting stent whose main body is made of a metal or a polymeric material, the surface of which is coated with a mixture including cilostazol and a bioabsorbable polymer, wherein the molecular weight of the bioabsorbable polymer is 40,000 to 600,000.

Claims

1. A drug-eluting stent having a net-like main body which is made of a metal or a polymeric material and has flection sections, wherein a surface of the main body is coated with a mixture comprising cilostazol and a bioabsorbable polymer, wherein the bioabsorbable polymer comprises (a) a polymer comprising DL lactide and glycolide in a weight ratio of 7:3-9:1, whose molecular weight is 40,000-400,000, (b) a polymer comprising DL lactide whose molecular weight is 50,000-100,000, (c) a polymer comprising L lactide and DL lactide in a weight ratio of 6:4-8:2, whose molecular weight is 300,000-600,000, (d) a polymer comprising L lactide whose molecular weight is 50,000-150,000, or (e) a polymer comprising L lactide and caprolactone in a weight ratio of 6:4-8:2, whose molecular weight is 150,000-400,000.

2. The drug-eluting stent as claimed in claim 1, wherein the bioabsorbable polymer comprises a polymer comprising DL lactide and glycolide in a weight ratio of 73:27-77:23, whose molecular weight is 63,000.

3. The drug-eluting stent as claimed in claim 1, wherein a weight ratio of cilostazol and the bioabsorbable polymer is 4:6-7:3.

4. The drug-eluting stent as claimed in claim 3 wherein the weight ratio of cilostazol and the bioabsorbable polymer is 4: 6-6:4.

5. The drug-eluting stent as claimed in claim 1, whose main body is made of a cobalt-chromium alloy as a main ingredient.

6. The drug-eluting stent as claimed in claim 1, wherein the mixture coated on the surface of the main body is coated by ultrasonic spraying.

7. The drug-eluting stent as claimed in claim 1, wherein the weight of the cilostazol applied on the stent is more than 400 μg and less than 700 μg.

8. The drug-eluting stent as claimed in claim 7, wherein the weight of the cilostazol applied on the stent is more than 500 μg and less than 600 μg.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1(a) shows a whole image of a stent, and FIG. 1(b) shows a cross-section view along the line A-A of FIG. 1(a).

(2) FIG. 2 shows an overview of coating a stent by means of a ultrasonic spray machine.

(3) FIG. 3 shows a faulty example of coating in Example 2 (web-like adduct).

(4) FIG. 4 shows a faulty example of coating in Example 2 (uneven coating).

(5) FIG. 5 shows the result of Example 2.

(6) FIG. 6 shows the result of Example 3.

(7) FIG. 7 shows the result of Example 4.

(8) FIG. 8 shows a drawing for explaining Example 5.

(9) FIG. 9 shows the intima-media/vascular-media ratio which is the result of Example 5.

(10) FIG. 10 shows the neointimal area which is the result of Example 5.

(11) FIG. 11 shows the endothelial coverage which is the result of Example 5.

DESCRIPTION OF EMBODIMENTS

(12) It is known that cilostazol used herein whose chemical name is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril has platelet aggregation inhibition action, phosphodiesterase (PDE) inhibition action, antiulcer, hypotensive action and antiphlogistic action, and is useful as an antithrombotic agent, a drug for improving cerebral circulation, an antiinflammatory agent, an antiulcer drug, an antihypertensive drug, an antiasthmatic drug, a phosphodiesterase inhibitor, etc. Cilostazol also encompasses its pharmaceutically acceptable salt.

(13) The bioabsorbable polymer used herein includes, for example, a polylactide comprising lactide and/or glycolide, whose molecular weight is 40,000 to 600,000. Specifically, the bioabsorbable polymer includes a polymer comprising DL lactide, L lactide, glycolide, caprolactone, etc., in more detail, (a) a polymer comprising DL lactide and glycolide in a weight ratio of 7:3-9:1, whose molecular weight is 40,000-400,000, (b) a polymer comprising DL lactide whose molecular weight is 50,000-100,000, (c) a polymer comprising L lactide and DL lactide in a weight ratio of 6:4-8:2, whose molecular weight is 300,000-600,000,

(14) (d) a polymer comprising L lactide whose molecular weight is 50,000-150,000, and (e) a polymer comprising L lactide and caprolactone in a weight ratio of 6:4-8:2, whose molecular weight is 150,000-400,000. Preferably, the bioabsorbable polymer includes the bioabsorbable polymers listed in Table 1 in the Example Section below, or a mixture thereof, more preferably RG858S, RG755S, LR704S, 755/703, or a mixture thereof.

(15) Coating agent 3 comprises a mixture of cilostazol as a medicament and the bioabsorbable polymer mentioned above. The bioabsorbable polymer needs to prevent the coating layer comprising cilostazol from removing because cilostazol is poorly water-soluble, and also needs to maintain a high coating strength.

(16) The mixture ratio by weight of cilostazol and polylactide is preferably 4:6-7:3. When the mixture ratio is within the range, it is expected to gain a good effect to suppress intimal thickening. And, when the mixture ratio is in 4:6-6:4, the coating strength can be further increased.

(17) The stent used herein is a normal stent made of a metal or a polymeric material. In case of a metal stent, the metal includes a suitable alloy of nickel, cobalt, chrome, titanium and/or stainless steel, preferably cobalt-chromium alloy as a main ingredient.

(18) The method for coating a stent with a mixture of cilostazol and bioabsorbable polymer in the present invention includes a conventional simplified spray method, a dipping method, an electrodeposition, a ultrasonic spray method, and the like, preferably a ultrasonic spray method from the viewpoint of the coating strength.

(19) Hereinafter, the embodiments of the present invention are illustrated showing the attached figures. The present inventors have extensively studied in order to solve the problem on conventional drug-eluting stents, and have found that it is possible to prepare a drug-eluting stent which can stably hold cilostazol on the stent and strongly suppress intimal thickening, by coating a metal stent or a polymeric material stent with cilostazol and the polymer mentioned below.

(20) FIG. 1 (a) is a view showing a drug-eluting stent of the present invention. FIG. 1 (b) is a cross-section view of FIG. 1 (a) along the line A-A. Stent 1 has a cylindrical lumen structure having a longer direction axis whose periphery has a net-like pattern, which can be expanded outward. A stent is inserted into a body in an un-expanded state, and then expanded at a treating-target site in a blood vessel to be indwelled in a blood vessel. The expansion may be achieved in a blood vessel with a balloon catheter. FIGS. 1(a) and 1(b) show a net-like pattern as a view, but the present invention can include other net-like patterns.

(21) As shown in FIG. 1 (b), stent 1 of the present invention is coated on base member 2 with coating agent 3. Base member 2 can be prepared in an arbitrary method. For example, it can be prepared from a midair stainless steel tube or a formed stainless steel tube by laser, electric discharge milling, chemical etching, or other methods. Base member 2 can be made of a suitable alloy of nickel, cobalt, chrome, titanium and/or stainless steel.

(22) FIG. 2 is a view showing ultrasonic spray coating machine 4 which applies coating agent 3 on base member 2. Before the coating step, the surface of base member 2 is plasma-treated with a plasma machine which is not shown in FIG. 2. After the plasma treatment, base member 2 is attached to a mandrel, which is fixed in ultrasonic spray coating machine 4. In ultrasonic spray coating machine 4, a liquid coating agent is sent through pipe 6 with a syringe pump, and then atomized and sprayed with ultrasonic spray nozzle 5. While spraying, base member 2 is rotated and linearly moved under ultrasonic spray nozzle 5 to pile up coating agent 3 on base member 2. Subsequently, base member 2 is rotated and linearly moved under nitrogen stream, and further dried in vacuo in a desiccator to prepare stent 1.

(23) The liquid coating agent used herein is a solution of cilostazol and the polymer in a solvent. The solvent used herein includes a volatile solvent having a low boiling point, which can be easily removed after the coating. The volatile solvent includes, for example, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, isoamyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methylene chloride, chloroform, dichloroethane, and a mixture of the two or more solvents.

EXAMPLE

(24) Each polymer listed in the following Table 1 was used in each example below.

(25) TABLE-US-00001 TABLE 1 Composition DL: DL lactide G: glycolide molecular L: L lactide weight C: caprolactone (a) ≈65,000 DL:G = 45:55-55:45 (b) ≈32,000 DL:G = 45:55-55:45 (c) ≈13,000 DL:G = 48:52-52:48 (d) ≈5,900 DL:G = 45:55-55:45 (e) ≈63,000 DL:G = 73:27-77:23 (f) ≈12,000 DL:G = 73:27-77:23 (g) ≈11,000 DL:G = 73:27-77:23 (h) ≈77,000 DL = 100 (i) ≈28,000 DL = 100 (j) ≈220,000 DL:G = 83:17-87:13 (k) ≥1,000,000 L:G = 82:18-88:12 (l) ≈115,000 DL = 100 (m) ≈257,000 L:C = 67:33-73:23 (n) ≥1,300,000 L:DL = 67:37-73:27 (o) ≥630,000 L:DL = 67:37-73:27 (p) ≥350,000 L:DL = 67:37-73:27 (q) ≈102,000 L = 100

Example 1

(26) A cobalt-chromium alloy as base member 2 was coated with a mixture of cilostazol and a polymer that was one of the above-listed (e), (j) and (p), wherein the mixing ratio of cilostazol and the polymer was varied as shown in Table 2, through ultrasonic spraying, and each coating strength was evaluated. The results are shown in Table 2. In the table, the symbol “0” indicates that the strength is very high, the symbol “Δ” indicate that the strength is high, and the symbol “x” indicates that the strength is low.

(27) The results indicate that when the mixture ratio of cilostazol and the polymer (D/P ratio) is 6:4 or less, i.e., the amount of cilostazol is less than this ratio, the strength is high, and in particular, when the ratio is 5:5, the strength is enough high. However, when the D/P ratio is less than 4:6, it is assumed that the drug effect of cilostazol used in a drug-eluting stent can decrease. Thus, the D/P ratio is preferably 4:6 or more.

(28) TABLE-US-00002 TABLE 2 polymer D/P mixed polymer ratio (e) (j) (P) (e):(p) strength (j):(p) strength 7/3 x Δ Δ 2:1 x 2:1 x 1.5:1.5 x 1.5:1.5 x 1:2 x 1:2 x 6/4 Δ Δ Δ 3:1 Δ 3:1 Δ 2:2 Δ 2:2 Δ 1:3 Δ 1:3 Δ 5/5 ∘ ∘ ∘ 1:4 ∘ 1:4 Δ 2.5:2.5 Δ 2.5:2.5 Δ 4:1 Δ 4:1 ∘

Example 2

(29) A cobalt-chromium alloy as base member 2 was coated with a coating agent prepared by mixing cilostazol and one of the 17 polymers (a) to (q) listed in Table 1, through ultrasonic spraying. The mixing ratio of cilostazol and each polymer was 5:5.

(30) The outer appearance of each prepared stent was observed about the coating work. In the external observation, coated stents having no web-like adduct shown in FIG. 3 or no uneven coating shown in FIG. 4 in the coated stents, and whose surface is not like orange peel but flat and smooth, were evaluated as “good”. The results are shown in FIG. 5. In FIG. 5, the axis of ordinate denotes the molecular weight of each polymer mixed with cilostazol and the axis of abscissas denotes the dissolution rate of the coating agent. The (a) to (q) indicated in FIG. 5 which are the 17 polymers listed in Table 1 show the relation of the two factors by their positions.

(31) As the evaluation of the coating performance, the polymers in the area circled with a ellipse in FIG. 5 exhibited a tendency of good coatings. FIG. 5 indicates that the coating performance cannot be greatly affected by the dissolution rate, but it tends to be affected by the molecular weight of the polymers. The polymer to be used in a coating agent comprising cilostazol is preferably a polymer having a molecular weight of 40,000-600,000. In particular, it was observed that polymers (e), (h), (j), (m), (p), and (q) in a coating agent can bring in a good coating performance.

Example 3

(32) Stents were prepared with the above polymers (e), (h), (j), (m), (p), and (q) in a similar manner to Example 2. As explained below, each prepared stent was placed in the iliac blood vessel of rabbits, and the effect of each stent to suppress intimal thickening was evaluated.

(33) First, the neck of a rabbit is incised, and the right carotid artery is exteriorized, to which an introducer is attached. A guidewire for balloon catheter is inserted from the introducer and moved under X-ray fluoroscopy to the distal portion of the iliac artery to be treated. And then, an angiographic catheter is inserted along the guidewire, and the angiography is performed at the disposing site of the iliac artery. After the angiography at the disposing site, a balloon catheter with the test stent is inserted to the disposing site along the guidewire for balloon catheter under X-ray fluoroscopy. The test stent (wherein the stent diameter is 2.75 mm when the standard diameter dilating pressure is 9 atm) is placed at the disposing site of the iliac artery (the blood vessel diameter is assumed to be 2.5 mm) and then the balloon is expanded with an indeflator holding the pressure of 14 atm (over-expanded, assumed stent diameter: 3.0 mm, 20% over-expanded) for 20 seconds one time. After confirming that the stent is expanded, the balloon is deflated, the indeflator is removed out, and the balloon catheter is pulled out along the guidewire for balloon catheter. The same procedure is performed at the right and left of the iliac artery.

(34) Next, the angiographic catheter is moved close to the disposing site along the guidewire for balloon catheter, and there the angiography is performed with a diluted contrast agent. The same procedure is performed at the right and left of the iliac artery, and then the angiographic catheter is pulled out. Finally, the blood vessel at the sheath insertion site is ligated, and the skin and muscle layer are sewn up. In this way, the stent can be placed in the iliac blood vessel of rabbits.

(35) The intimal thickening was tested by observing the stent-placed site with the angiographic pictures recorded on DVD before the placement, shortly after the placement of the stent (reference diameter), and before the autopsy (28 days after the placement). And the intimal thickening was evaluated based on the difference between the reference diameter shortly after the placement of the stent and the narrowest blood vessel diameter before the autopsy.

(36) FIG. 6 shows the results. The term “no drug” in FIG. 6 means that the stent is not coated with cilostazol. The other results are based on the stents which are coated with each coating agent comprising mixtures the above polymers and cilostazol in a ratio of 5:5.

(37) The axis of ordinate in FIG. 6 denotes the intimal thickening, i.e., when the length is smaller, it means that the effect of suppressing intimal thickening is higher.

(38) The result of (j) which includes cilostazol shows that the intimal thickening is greatly suppressed. Similarly, the results of (e) and (p) also showed that the coating with cilostazol can suppress intimal thickening. In addition, the observation of the endothelial cells at the stent-placing site showed that the endothelial cells could be well regenerated, and thus, the present stent coated with cilostazol was able to achieve the both effects of (1) suppressing intimal thickening and (2) suppressing the inhibitory of the vascular endothelial cell regeneration, which have not been achieved with limus-type drugs.

Example 4

(39) Stents were prepared with the above polymer (e), which were different at the mixture ratio of cilostazol (D) and the polymer (P) (D/P ratio). The prepared stents were placed in the iliac blood vessel of rabbits, and the effect of each stent to suppress intimal thickening was evaluated. The results are shown in FIG. 7.

(40) The results show that both the stents having the mixture ratio (D/P ratio) of 4:6 or 7:3 could suppress intimal thickening more than the stent composed of only the base member (BMS) or the stent coated with only the polymer.

(41) In addition, the observation of the endothelial cells at the stent-placing site showed that the endothelial cells could be well regenerated, and thus, the present stent coated with cilostazol was able to achieve the both effects of (1) suppressing intimal thickening and (2) suppressing the inhibitory of the vascular endothelial cell regeneration, which have not been achieved with limus-type drugs.

Example 5

(42) Similarly, stents were prepared with the above polymer (e), wherein the mixture ratio of cilostazol and polymer (e) (D/P ratio) is fixed at 5:5, but the weight of cilostazol varied between 300 μg-600 μg. The prepared stents were placed in the iliac blood vessel of swine, and then (I) intima-media/vascular-media ratio, (II) neointimal area, and (III) vascular endothelial cell coverage, at the stent-placing site of the iliac blood vessel were evaluated 28 days after the placement.

(43) The (II) neointimal area here denotes the cross-section area of intima-media 81 which is newly formed in the inside of blood vessel 80 at the stent-placing site, as shown in FIG. 8. The (I) intima-media/vascular-media ratio denotes the ratio of the above neointimal area to the cross-section area of vascular-media 82.

(44) The evaluation was performed as follows:

(45) (a) pulling out the iliac blood vessel,

(46) (b) washing it, and then delipidating it,

(47) (c) penetrating a resin, and then immobilizing it by polymerizing the resin,

(48) (d) cutting it at the intended site, and

(49) (e) staining it, and then observing it by microscopy.

(50) FIG. 9 shows each (I) intima-media/vascular-media ratio determined varying the weight of cilostazol. The upper of the figure shows pictures of each blood vessel cross-section which were taken 28 days after placing a stent loaded with each weight of cilostazol in the blood vessel. The data indicated by “BMS” herein is a result obtained by using a metal stent which is not coated with any drug or polymer.

(51) According to FIG. 9, when the weight of cilostazol is more than 400 μg, the intima-media/vascular-media ratio falls to well below 100%, which indicates that the generation of the intima-media can be suppressed at the stent-placing site. In particular, when the weight of cilostazol is 500 μg or 600 μg, the intimal thickening can be significantly suppressed, compared with the case of the stent composed of only the base member (BMS) whose intima-media/vascular-media ratio is more than 260%.

(52) However, when the weight of cilostazol is too much, the amount of the polymer needs to be increased. In such a case, the total amount of the coating agent should be swollen, and thereby it becomes difficult to form a strong and uniform coating. In addition, the result in FIG. 9 shows that the reduction of intima-media/vascular-media ratio has peaked when the weight of cilostazol is 500 μg-600 μg. Thus, the amount of cilostazol is preferably more than 400 μg and less than 700 μg, and in particular, more preferably more than 500 μg and less than 600 μg.

(53) FIG. 10 shows each (II) neointimal area determined varying the weight of cilostazol. FIG. 10 indicates that any cases of the stents coated with cilostazol can reduce the neointimal area, compared with the case of the stent composed of only the base member (BMS), and in particular, when the weight of cilostazol is more than 400 μg, the neointimal area is reduced a lot. In particular, when the weight of cilostazol is 600 μg, the neointimal area is significantly reduced, compared with the case of the stent composed of only the base member (BMS).

(54) FIG. 11 shows each (III) vascular endothelial cell coverage determined varying the weight of cilostazol. The result indicates that the coating with cilostazol and the polymer can make the vascular endothelial formulation easy at any weight of cilostazol, compared with the case of the stent composed of only the base member (BMS).

(55) As shown at the results in FIG. 9-FIG. 11, the present invention can suppress intimal thickening at the stent-placing site, and prevent inhibiting the vascular endothelial cell regeneration. Thus, the amount of cilostazol is preferably more than 400 μg and less than 700 μg, and in particular, more preferably more than 500 μg and less than 600 μg.

EXPLANATIONS OF LETTERS OR NUMERALS

(56) 1: stent

(57) 2: base member

(58) 3: coating agent

(59) 4: ultrasonic spray coating machine

(60) 5: ultrasonic spray nozzle

(61) 6: pipe

(62) 80: cross-section of blood vessel

(63) 81: intima-media

(64) 82: vascular-media