KR102718304B1 - Pretreatment method for bioresorbable stent - Google Patents

Abstract

The method for manufacturing a biodegradable stent of the present invention comprises a step of pretreating a non-pretreated 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 a link strut and damage ratio of an axial strut, and increasing 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.

Description

{Pretreatment method for bioresorbable stent}

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

A stent is a medical device that is inserted into a narrowed area in the body to expand the narrowed lumen. The stent can be delivered to a desired location in the body cavity in an unexpanded state and can then expand on its own or by internal radial forces.

After crimping the stent to secure it to the catheter, cracks may occur on the surface at a certain rate during the process of expanding it, and the mechanical properties of the stent may deteriorate as the struts are damaged. Therefore, research on the pretreatment process of the stent was needed to compensate for this.

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 a non-pretreated 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 a crack occurring in the crimping step is healed through the pretreatment step. The biodegradable stent manufactured according to the above manufacturing method can have improved mechanical properties as the cracks on the surface are healed, and the radial strength of the stent increases.

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

All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific description below.

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 (BRS) comprising a first biodegradable polymer using an inflatable balloon; detaching the crimped stent and the inflatable 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.

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

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

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 method for manufacturing a biodegradable stent may be characterized in that the organic solvent is THF or acetone.

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

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).

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.

One embodiment of the present invention relates to a biodegradable stent manufactured by 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.

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

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.

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.

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.

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 3,500 to 3,700 mbar/mm based on the force observed at a crimper diameter of 1.5 mm.

The method for manufacturing a biodegradable stent of the present invention comprises a step of pretreating a non-pretreated 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 a link strut and damage ratio of an axial strut, and increasing 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.

Figure 1 shows cracks and damage of struts for a stent expanded under NP conditions using a pretreatment solution containing THF in the pretreatment step.
Figure 2 shows cracks and damage of struts for stents expanded under RBP conditions using a pretreatment solution containing THF in the pretreatment step.
Figure 3 shows cracks and damage of struts for a stent expanded under NP conditions using a pretreatment solution containing acetone in the pretreatment step.
Figure 4 shows cracks and damage in the struts of a stent expanded under RBP conditions using a pretreatment solution containing acetone in the pretreatment step.
Figure 5 shows cracks and damage in the struts for the stent expanded under NP conditions without any pretreatment step.
Figure 6 shows cracks and damage in the struts for the stent expanded under RBP conditions without any pretreatment step.
Figure 7 shows the average radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under NP expansion conditions.
Figure 8 shows the average radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under RBP expansion conditions.

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.

In the manufacture of stents, the pretreatment step can play a role in preventing defects such as surface cracks. After the stent is first crimped, the crack created by the crimping can be healed through pretreatment, and then the stent can be provided by crimping again after drug coating to be connected to a catheter. Before crimping and expansion of a biodegradable stent, the surface crack can be healed with a biodegradable polymer having excellent biocompatibility. The crack on the surface of the stent can be healed by dissolving the crack with an organic solvent. Another method for healing the crack on the surface of the stent can be a process of filling the crack with a polymer. By healing the crack, cracks, fractures, and damage of the strut can be prevented in the subsequent crimping and expansion steps, and the radial force can be increased.

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%.

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

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.

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.

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 the cracks on the surface of the stent, and the cracks of the stent may be filled with a second biodegradable polymer. In the process, the pretreatment solution may 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.

According to one embodiment of the present invention, after the pretreatment step, a step of drying the stent, on which the pretreatment has been completed, 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.

One embodiment of the present invention relates to a biodegradable stent manufactured by 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. The biodegradable stent of the present invention may have a crack healed on the surface of the biodegradable stent according to the pretreatment step.

According to one embodiment of the present invention, the ratio of cracks in the link strut may be 1.2% or 0.3% or less. The biodegradable stent of the present invention has an effect in which cracks in the link strut hardly occur through the pretreatment step, which leads to improvement in mechanical properties.

According to one embodiment of the present invention, when expanded at a 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 a 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 gone through.

According to one embodiment of the present invention, when expanded at an 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 an 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 a pretreatment step compared to a case where the pretreatment step is not gone through.

Hereinafter, the present invention will be described in detail by way of examples in order to specifically explain the present invention. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention is not construed as being limited to the examples described below. The examples in this specification are provided to more completely explain the present invention to a person having average knowledge in the art.

Manufacturing example: Pretreatment process of stent

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

(1) After crimping the PLLA-based BRS stent using a catheter, the stent was detached from the expandable balloon of the catheter. (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 at room temperature overnight. (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 at room temperature overnight. (6) Each stent was crimped using a catheter.

According to the above process, six samples were prepared by pretreatment with a pretreatment solution containing acetone (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) and coating only the BRS drug coating solution (Preparation Example 3).

Example: Expansion of stent samples

To evaluate the difference in the appearance of the stents according to the preprocessing method, six BRS stents that had been crimped were prepared for each group. Three of the stents loaded into the catheter 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, and these are summarized in Table 1 below.

[Table 1]

Experimental Example 1. Appearance Evaluation of Stent

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

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

The degree of damage in each group was compared, and the results were compared according to whether or not pretreatment was performed. The results of comparing the degree of damage according to the type of solution used in the pretreatment process are summarized in Table 2 .

[Table 2]

When the results of the appearance evaluation were compared to select a pretreatment solution suitable for the BRS stent, the degree of damage to the axial strut 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.

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 link strut crack ratios of 0.30%, Example 4 and Comparative Example 2 had link strut crack ratios of 0.89%, and Comparative Example 5 had link strut crack ratios of 1.19%. In the case of webbing, Examples 1 to 6 (Group B) and Examples 7 to 12 (Group C) were similar.

Experimental Example 2. Evaluation of the radial force of the stent

In order to evaluate the radial force of stents according to the pretreatment method (radial force test), 6 stents (3 NP expansions and 3 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 the 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 measurement unit was mbar/mm. The radial force for each group was organized in Table 3 below, and graphed as in Figs. 7 and 8. Fig. 7 shows the average value of the radial force measured as the crimper diameter changed from 4.0 mm to 1.5 mm under the NP expansion condition. Figure 8 shows the average radial force measured as the diameter of the crimper changes from 4.0 mm to 1.5 mm under RBP expansion conditions.

[Table 3]

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 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.

As a result of the appearance evaluation, it was found that the damage to the shaft 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 is desirable to use a pretreatment solution containing THF, like Group C.

Claims (14)

A step of crimping a non-pretreated bioresorbable stent (BRS) 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 containing a drug; and
A step of coating a pretreated stent with a drug-coating solution;
Including,
The above crimping is done by compressing with a crimper,
A method for manufacturing a biodegradable stent, wherein the organic solvent is THF. A method for manufacturing a biodegradable stent, characterized in that in claim 1, the pretreatment solution additionally contains a second biodegradable polymer. A method for manufacturing a biodegradable stent, characterized in that in claim 1, the pretreatment solution does not contain a biodegradable polymer. delete delete delete A method for manufacturing a biodegradable stent, characterized in that in claim 1, the first biodegradable polymer comprises 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). 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. 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 containing a drug; and
A step of coating a pretreated stent with a drug-coating solution;
Including,
The above crimping is done by compressing with a crimper,
A biodegradable stent manufactured according to a method for manufacturing a biodegradable stent, wherein the organic solvent is THF. A biodegradable stent characterized in that, in claim 9, cracks on the surface of the biodegradable stent are healed according to the pretreatment step. A biodegradable stent according to claim 9, characterized in that the manufactured biodegradable stent has a radial force of 3800 to 4700 mbar/mm based on the force observed at a crimper diameter of 1.5 mm when expanded at a nominal pressure (NP) of 8 atm. 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. A biodegradable stent according to claim 9, wherein the biodegradable stent has a radial force of 3200 to 4000 mbar/mm based on the force observed at a crimper diameter of 1.5 mm when expanded at a RBP (Rated Burst Pressure) of 16 atm. A biodegradable stent according to claim 13, wherein the biodegradable stent has a radial force of 3,500 to 3,700 mbar/mm based on the force observed at a crimper diameter of 1.5 mm when expanded at an RBP of 16 atm.