Pretreatment method of bioresorbable stent

Abstract

The method for manufacturing a bioresorbable stent, of the present invention, comprises a step of pretreating a non-pretreated stent containing a bioresorbable polymer with a pretreatment solution containing an organic solvent, thereby healing cracks in the surface of the biodegradable stent manufactured by the method, improving mechanical properties, reducing the proportions of cracks in link struts and damage of axial struts, and increasing the radial force. The biodegradable stent manufactured according to the method for manufacturing a biodegradable stent of the present invention has improved mechanical properties, and thus can be safely placed in the body of a patient.

Description

Pretreatment method for biodegradable stents

[0001] The present invention relates to a method for pretreating a surface in manufacturing a bioresorbable stent (BRS).

[0002] A stent is a medical device inserted into a narrowed area within the body to expand the narrowed lumen. Stents can be delivered to a desired location within a body cavity in an uninflated state and then expanded either on their own or by internal radial forces.

[0003] After crimping a stent to secure it to a catheter, the process of expanding it can lead to surface cracks at a certain rate, and damage to the struts can deteriorate the stent's mechanical properties. Therefore, research on a stent pretreatment process to address these issues is needed.

[0004] The technical problem to be achieved by the present invention is to provide a method for manufacturing a biodegradable stent, which comprises a step of pretreating an untreated stent containing a biodegradable polymer with a pretreatment solution containing an organic solvent. The biodegradable stent is characterized in that it comprises a crimping step prior to the pretreatment step, and cracks generated in the crimping step are healed through the pretreatment step. The biodegradable stent manufactured according to the manufacturing method can have improved mechanical properties as the surface cracks are healed, and the radial strength of the stent is increased.

[0005] However, the problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0006] All combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific description below.

[0007] One embodiment of the present invention relates to a method for manufacturing a biodegradable stent, comprising the steps of: crimping a non-pretreated biodegradable stent (Bioresorbable Stent, BRS) containing a first biodegradable polymer using an inflatable balloon; detaching the crimped stent and the inflatable balloon; pretreating the detached stent with a pretreatment solution containing an organic solvent but not containing a drug; and coating the pretreated stent with a drug coating solution.

[0008] According to one embodiment of the present invention, the pretreatment solution may additionally contain a second biodegradable polymer.

[0009] According to one embodiment of the present invention, the pretreatment solution may not contain a biodegradable polymer.

[0010] According to one embodiment of the present invention, the organic solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethylacetamide (DMAC), acetone, ethanol, and combinations thereof.

[0011] According to one embodiment of the present invention, the method for manufacturing a biodegradable stent may be characterized in that the organic solvent is THF or acetone.

[0012] According to one embodiment of the present invention, the method for manufacturing a biodegradable stent may be characterized in that the organic solvent is THF.

[0013] According to one embodiment of the present invention, the first biodegradable polymer may be composed of at least one selected from the group consisting of poly(lactide-co-ε-caprolactone, PLCL), poly(lactide-co-glycolide, PLGA), polyglycolide (PGA), poly-L-lactic acid (PLLA), poly-D,L-lactic acid (PDLLA), and poly-ε-caprolactone (PCL).

[0014] According to one embodiment of the present invention, the second biodegradable polymer may be composed of at least one selected from the group consisting of PLCL, PLGA, PGA, PLLA, PDLLA, and PCL.

[0015] One embodiment of the present invention relates to a biodegradable stent manufactured according to a method for manufacturing a biodegradable stent, the method comprising: crimping a non-pretreated biodegradable stent comprising a first biodegradable polymer using an expandable balloon; detaching the crimped stent and the expandable balloon; pretreating the detached stent with a pretreatment solution comprising an organic solvent but not a drug; and coating the pretreated stent with a drug coating solution.

[0016] According to one embodiment of the present invention, cracks on the surface of the biodegradable stent may be healed according to the pretreatment step.

[0017] According to one embodiment of the present invention, when the manufactured biodegradable stent is expanded at a nominal pressure (NP) of 8 atm, it may have a radial force of 3800 to 4700 mbar / mm based on the force observed at a crimper diameter of 1.5 mm.

[0018] According to one embodiment of the present invention, when the manufactured biodegradable stent is expanded at an NP of 8 atm, it may have a radial force of 4200 to 4300 mbar / mm based on the force observed at a crimper diameter of 1.5 mm.

[0019] According to one embodiment of the present invention, when the manufactured biodegradable stent is expanded at a rated burst pressure (RBP) of 16 atm, it may have a radial force of 3200 to 4000 mbar / mm based on the force observed at a crimper diameter of 1.5 mm.

[0020] According to one embodiment of the present invention, when the manufactured biodegradable stent is expanded at an RBP of 16 atm, it may have a radial force of 3500 to 3700 mbar / mm based on the force observed at a crimper diameter of 1.5 mm.

[0021] The method for manufacturing a biodegradable stent of the present invention includes a step of pretreating an untreated stent containing a biodegradable polymer with a pretreatment solution containing an organic solvent, thereby healing cracks on the surface of the biodegradable stent manufactured thereby, improving mechanical properties, reducing the crack ratio of the link strut and the damage ratio of the axial strut, and increasing the radial force. The biodegradable stent manufactured according to the method for manufacturing a biodegradable stent of the present invention has improved mechanical properties, thereby enabling the stent to be safely positioned in a patient's body.

[0022] Figure 1 shows cracks and damage of struts for stents expanded under NP conditions using a pretreatment solution containing THF in the pretreatment step.

[0023] Figure 2 shows cracks and damage of struts for stents expanded under RBP conditions using a pretreatment solution containing THF in the pretreatment step.

[0024] Figure 3 shows cracks and damage of struts for stents expanded under NP conditions using a pretreatment solution containing acetone in the pretreatment step.

[0025] Figure 4 shows cracks and damage of struts for stents expanded under RBP conditions using a pretreatment solution containing acetone in the pretreatment step.

[0026] Figure 5 shows cracks and damage in the struts for the stent expanded under NP conditions without any pretreatment step.

[0027] Figure 6 shows cracks and damage in the struts for the stent expanded under RBP conditions without any pretreatment step.

[0028] Figure 7 shows the average values ​​of the radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under NP expansion conditions.

[0029] Figure 8 shows the average values ​​of the radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under RBP expansion conditions.

[0030] One embodiment of the present invention relates to a method for manufacturing a biodegradable stent, comprising the steps of: crimping a non-pretreated biodegradable stent comprising a first biodegradable polymer using an expandable balloon; detaching the crimped stent and the expandable balloon; pretreating the detached stent with a pretreatment solution comprising an organic solvent but not a drug; and coating the pretreated stent with a drug coating solution.

[0031] In stent manufacturing, the pretreatment step can prevent defects such as surface cracks. After the stent is first crimped, the cracks created by the crimping process can be healed through pretreatment. After drug coating, the stent can be re-crimped to provide a stent attached to a catheter. Prior to crimping and expansion of a biodegradable stent, surface cracks can be healed with a biodegradable polymer with excellent biocompatibility. The cracks on the stent surface can be healed by dissolving them in an organic solvent. Another method for healing the cracks on the stent surface can be a process of filling them with a polymer. By healing the cracks, the struts can be prevented from cracking, fracture, and damage during the subsequent crimping and expansion steps, and the radial strength can be increased.

[0032] According to one embodiment of the present invention, the pretreatment solution may further comprise a second biodegradable polymer. According to one embodiment of the present invention, the second biodegradable polymer may be composed of at least one selected from the group consisting of PLCL, PLGA, PGA, PLLA, PDLLA, and PCL. The second biodegradable polymer may be PDLLA. According to one embodiment of the present invention, the concentration of the second biodegradable polymer in the pretreatment solution may be 0.01 to 5.0% or 0.1 to 1.0%. According to one embodiment of the present invention, the concentration of the second biodegradable polymer in the pretreatment solution may be about 0.3%.

[0033] According to one embodiment of the present invention, the pretreatment solution may not contain a biodegradable polymer. The pretreatment process may heal cracks on the surface of the stent by dissolving the cracks with an organic solvent without providing an additional biodegradable polymer.

[0034] According to one embodiment of the present invention, the organic solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethylacetamide (DMAC), acetone, ethanol, and combinations thereof. According to one embodiment of the present invention, the organic solvent may be THF or acetone. According to one embodiment of the present invention, the organic solvent may be THF.

[0035] According to one embodiment of the present invention, the first biodegradable polymer may be composed of at least one selected from the group consisting of poly(lactide-co-ε-caprolactone, PLCL), poly(lactide-co-glycolide, PLGA), polyglycolide (PGA), poly-L-lactic acid (PLLA), poly-D,L-lactic acid (PDLLA), and poly-ε-caprolactone (PCL). The first biodegradable polymer may be PLLA or PDLLA.

[0036] According to one embodiment of the present invention, the pretreatment step may be in the form of spraying a pretreatment solution containing an organic solvent onto the surface of a biodegradable stent that has not been pretreated. As the pretreatment solution is sprayed onto the surface of the biodegradable stent, the pretreatment solution may reach cracks on the surface of the stent, and the second biodegradable polymer may fill the cracks of the stent. In the process, the pretreatment solution may also partially dissolve the first biodegradable polymer in the cracks of the stent. The pretreatment solution may partially dissolve the first biodegradable polymer present in the cracks of the stent, and when dried, the second biodegradable polymer may fill the cracks.

[0037] According to one embodiment of the present invention, after the pretreatment step, a step of drying the pretreated stent at 40 to 60°C for 0.5 to 3 hours and then drying it at room temperature overnight may be additionally included. The drying temperature may be 45 to 55°C or about 50°C. The drying time may be 0.5 to 2 hours or about 1 hour.

[0038] One embodiment of the present invention relates to a biodegradable stent manufactured according to a method for manufacturing a biodegradable stent, the method comprising the steps of: crimping a non-pretreated biodegradable stent comprising a first biodegradable polymer using an expandable balloon; detaching the crimped stent and the expandable balloon; pretreating the detached stent with a pretreatment solution comprising an organic solvent but not a drug; and coating the pretreated stent with a drug coating solution. The biodegradable stent of the present invention may have a crack on the surface of the biodegradable stent healed according to the pretreatment step.

[0039] According to one embodiment of the present invention, the crack ratio of the link strut may be 1.2% or 0.3% or less. The biodegradable stent of the present invention has the effect of hardly generating cracks in the link strut after undergoing a pretreatment step, which results in improved mechanical properties.

[0040] According to one embodiment of the present invention, when expanded at NP of 8 atm, the damage ratio of the axial strut may be 15, 14, 13, 12, 11, or 10% or less. According to one embodiment of the present invention, when expanded at RBP of 16 atm, the damage ratio of the axial strut may be 15, 14, 13, 12, 11, or 10% or less. The biodegradable stent of the present invention has an effect of reducing the damage ratio of the axial strut during expansion by going through the pretreatment step compared to a case where the pretreatment step is not performed.

[0041] According to one embodiment of the present invention, when expanded at NP of 8 atm, it may have a radial force of 3800 to 4700 mbar / mm based on the force observed at a crimper diameter of 1.5 mm. The radial force may be 4200 to 4300 mbar / mm, about 4250 mbar / mm or more, or about 4250 mbar / mm. According to one embodiment of the present invention, when expanded at RBP of 16 atm, it may have a radial force of 3200 to 4000 mbar / mm based on the force observed at a crimper diameter of 1.5 mm. The radial force may be 3500 to 3700 mbar / mm, about 3650 mbar / mm or more, or about 3650 mbar / mm. The biodegradable stent of the present invention has an effect of increasing the radial force during NP expansion and RBP expansion by going through the pretreatment step compared to a case where the pretreatment step is not performed.

[0042] Hereinafter, the present invention will be described in detail using examples. However, the examples according to the present invention may be modified in various ways, and the scope of the present invention is not limited to the examples described below. The examples in this specification are provided to more fully explain the present invention to those of ordinary skill in the art.

[0043] Manufacturing example: Pretreatment process for stents

[0044] To evaluate the properties of stents according to the pretreatment process of the stent, samples were manufactured according to the following steps.

[0045] (1) After crimping the PLLA-based BRS stent using a catheter, the stent was detached from the catheter's expandable balloon. (2) The detached stent was pretreated with a pretreatment solution containing acetone solvent. (3) The pretreated stent was dried at 50°C for 1 hour and then dried overnight at room temperature. (4) The pretreated and dried stent was coated with a BRS drug-coating solution. (5) The drug-coated stent was dried at 50°C for 1 hour and then dried overnight at room temperature. (6) Each stent was crimped using a catheter.

[0046] Six samples were prepared by pretreatment with a pretreatment solution containing acetone according to the above process (Preparation Example 1). Six samples were prepared by using a pretreatment solution containing THF instead of acetone in the above process and using the same method as before (Preparation Example 2). For the control group, six BRS samples were prepared by omitting the pretreatment processes (1) to (3) above and coating only with the BRS drug coating solution (Preparation Example 3).

[0047] Example: Expansion of stent samples

[0048] To evaluate the differences in stent appearance according to pretreatment method, six crimped BRS stents were prepared for each group. Three of the catheter-loaded stents were expanded to the nominal pressure (NP) of 8 atm, and the other three were expanded to the rated burst pressure (RBP) of 16 atm. These results are summarized in Table 1.

[0049] [Table 1]

[0050]

[0051] Experimental Example 1. Appearance Evaluation of Stents

[0052] The appearance of the stents of Examples 1 to 18 was examined under a microscope. Images of areas where cracks or fractures appeared were taken, and the number of damages per area was recorded by dividing them into link struts and axial struts.

[0053] Fig. 1 shows cracks and damage of a strut for Example 1. Fig. 1 (a) shows a crack of a link strut, and (b) shows damage of an axis strut. Fig. 2 shows cracks and damage of a strut for Example 4. Fig. 2 (a) shows a crack of a link strut, and (b) shows damage of an axis strut. Fig. 3 shows cracks and damage of a strut for Example 7. Fig. 3 (a) shows no crack of a link strut, and (b) shows damage of an axis strut. Fig. 4 shows cracks and damage of a strut for Example 12. Fig. 4 (a) shows no crack of a link strut, and (b) shows damage of an axis strut. Fig. 5 shows cracks and damage of a strut for Comparative Example 2. Fig. 5 (a) shows a crack of a link strut, and (b) shows It shows damage to the shaft strut. Fig. 6 shows cracks and damage to the strut for comparative example 5. Fig. 6 (a) shows cracks in the link strut, and (b) shows damage to the shaft strut.

[0054] The degree of damage in each group was compared, and the results were compared according to the presence or absence of pretreatment. The results comparing the degree of damage according to the type of solution used in the pretreatment process are summarized in Table 2.

[0055] [Table 2]

[0056]

[0057] When the results of the appearance evaluation were compared to select a pretreatment solution suitable for the BRS stent, the degree of axial strut damage of Examples 1 to 6 (pretreatment solution containing acetone, Group B) and Examples 7 to 12 (pretreatment solution containing THF, Group C) was similar, but it was confirmed that Examples 7 to 12 (Group C) showed a tendency to be slightly reduced.

[0058] In the case of link strut cracks, both Examples 1 to 6 (Group B) and Examples 7 to 12 (Group C) were less than Comparative Examples 1 to 3 (Group A). ​​In particular, strut cracks were observed in some samples in Examples 1 to 6 (Group B), but not in Examples 7 to 12 (Group C). It was confirmed that there were 336 link struts in one stent, and Examples 1 and 3 and Comparative Examples 1, 4, and 6 had a link strut crack ratio of 0.30%, Example 4 and Comparative Example 2 had a link strut crack ratio of 0.89%, and Comparative Example 5 had a link strut crack ratio of 1.19%. In the case of webbing, Examples 1 to 6 (Group B) and Examples 7 to 12 (Group C) were similar.

[0059]

[0060] Experimental Example 2. Evaluation of the radial force of a stent

[0061] To evaluate the radial force of stents according to the pretreatment method (radial force test), six stents (three NP expansions and three RBP expansions) that had completed the appearance evaluation were prepared for each group. The crimper temperature for the radial force evaluation was maintained at 37℃, and calibration for dimensional and force measurements was performed. The stent was placed inside the crimper and left to stand for 1 minute. The crimper was set to compress at a speed of 0.5 mm / s from 4.0 mm to 1.5 mm in diameter, and the equipment was operated. The radial force was graphed based on the force observed at a diameter of 1.5 mm, and the unit of measurement was mbar / mm. The radial force for each group is summarized in Table 3 below and presented in a graph as shown in Figs. 7 and 8. Fig. 7 shows the average value of the radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under NP expansion conditions. Fig. 8 shows the average value of the radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under RBP expansion conditions.

[0062] [Table 3]

[0063]

[0064] The radial force of the samples of Examples 1 to 6 (Group B) and Examples 7 to 12 (Group C) was compared by expanding them to NP and RBP, and the radial force was found to be higher in Examples 7 to 12 (Group C) for both NP and RBP. In particular, the radial force of Examples 7 to 9 under NP conditions was significantly higher than that of Examples 1 to 3.

[0065]

[0066] As a result of the appearance evaluation, it was found that the damage to the axial strut of Examples 7 to 12 (Group C) was reduced compared to Examples 1 to 6 (Group B), and the radial force was also higher, so it was confirmed that it was desirable to use a pretreatment solution containing THF, as in Group C.

Claims

1. A step of crimping a non-pretreated bioresorbable stent (BRS) containing a first biodegradable polymer using an inflatable balloon; Step of detaching the crimped stent and the expandable balloon; A step of pretreating the detached stent with a pretreatment solution containing an organic solvent but not a drug; and A step of coating a pretreated stent with a drug-coating solution; A method for manufacturing a biodegradable stent comprising:

2. A method for manufacturing a biodegradable stent, characterized in that the pretreatment solution further comprises a second biodegradable polymer in the first paragraph.

3. A method for manufacturing a biodegradable stent, characterized in that the pretreatment solution in paragraph 1 does not contain a biodegradable polymer.

4. A method for manufacturing a biodegradable stent, characterized in that in paragraph 1, the organic solvent is selected from the group consisting of N,N-dimethylformamide (N,N-dimethylformamide, DMF), tetrahydrofuran (THF), dimethylacetamide (DMAC), acetone, ethanol, and combinations thereof.

5. A method for manufacturing a biodegradable stent, characterized in that in paragraph 4, the organic solvent is THF or acetone.

6. A method for manufacturing a biodegradable stent, characterized in that in paragraph 5, the organic solvent is THF.

7. A method for manufacturing a biodegradable stent, characterized in that in the first paragraph, the first biodegradable polymer is composed of at least one selected from the group consisting of poly(lactide-co-ε-caprolactone, PLCL), poly(lactide-co-glycolide, PLGA), polyglycolide (PGA), poly-L-lactic acid (PLLA), poly-D,L-lactic acid (PDLLA), and poly-ε-caprolactone (PCL).

8. A method for manufacturing a biodegradable stent, characterized in that in the second paragraph, the second biodegradable polymer is composed of at least one selected from the group consisting of PLCL, PLGA, PGA, PLLA, PDLLA, and PCL.

9. A step of crimping a non-pretreated biodegradable stent comprising a first biodegradable polymer using an inflatable balloon; Step of detaching the crimped stent and the expandable balloon; A step of pretreating the detached stent with a pretreatment solution containing an organic solvent but not a drug; and A step of coating a pretreated stent with a drug-coating solution; A biodegradable stent manufactured according to a method for manufacturing a biodegradable stent including:

10. A biodegradable stent characterized in that cracks on the surface of the biodegradable stent are healed according to the pretreatment step in paragraph 9.

11. A biodegradable stent characterized in that, in claim 9, when the manufactured biodegradable stent is expanded at a nominal pressure (NP) of 8 atm, it has a radial force of 3800 to 4700 mbar / mm based on the force observed at a crimper diameter of 1.5 mm.

12. A biodegradable stent according to claim 11, characterized in that the manufactured biodegradable stent has a radial force of 4200 to 4300 mbar / mm based on the force observed at a crimper diameter of 1.5 mm when expanded at an NP of 8 atm.

13. A biodegradable stent having a radial force of 3200 to 4000 mbar / mm based on the force observed at a crimper diameter of 1.5 mm when the manufactured biodegradable stent is expanded at a RBP (Rated Burst Pressure) of 16 atm in accordance with paragraph 9.

14. A biodegradable stent according to claim 13, wherein the biodegradable stent has a radial force of 3500 to 3700 mbar / mm based on the force observed at a crimper diameter of 1.5 mm when expanded at an RBP of 16 atm.

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