CA3182829A1 - Biodegradable composite material composition for manufacturing stent and manufacturing method thereof - Google Patents

Abstract

The present disclosure relates to a biodegradable composite material composition for manufacturing a stent and a manufacturing method thereof. The biodegradable composite material composition for manufacturing the stent of an exemplary embodiment of the present disclosure may be manufactured by a low-temperature sol-gel method to reduce physical and/or chemical damage to a biodegradable resin that is weak to heat, and has excellent physical properties when extruding a stent tube, thus making it easy to process.

Description

BIODEGRADABLE COMPOSITE MATERIAL COMPOSITION FOR
MANUFACTURING STENT AND MANUFACTURING METHOD THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Korean Patent Application No. 10-2021-0169090 filed in the Korean Intellectual Property Office on November 30, 2021, the entire contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present disclosure relates to a biodegradable composite material composition for manufacturing a stent and a manufacturing method thereof.
BACKGROUND ART
A medical stent is a medical apparatus that is used to perform a procedure inside blood vessels to dilate the blood vessels when blood circulation is poor due to narrowing of the blood vessels caused by various diseases occurring in the human body.
Specifically, a stent is a medical apparatus that is used to perform a procedure inside blood vessels to dilate the blood vessels when blood circulation is poor due to narrowing of the blood vessels caused by various diseases occurring in the human body.
Although there are several methods of medical procedures using a stent, it is mainly used to perform a procedure by balloon dilatation, which is designed to be inserted together with a balloon catheter into blood vessels such as cardiovascular, aorta, and cerebrovascular vessels to dilate the coronary passage as the balloon is inflated. The existing stents require elasticity and ductility in order to dilate outward and dilate to the size of the original vascular passage as the balloon is inflated. That is to say, the stent Date Recue/Date Received 2022-11-25 requires ductility for insertion into complex and twisted passages during the procedure of dilating the balloon to dilate the stenosed site after inserting the balloon catheter and fixing the same at a target site. In addition, after the procedure is finished, conditions such as elasticity are required to prevent deformation of the stent structure by the force of contraction of blood vessel (cardiovascular, aorta, cerebral artery, etc.) tissues. In addition, the material constituting the stent is required to have excellent biochemical properties such as high biocompatibility and stability for the human body and chemical properties such as high corrosion resistance.
In particular, in the case of a metal cardiovascular stent, the biocompatibility of the metal material is poor and there are side effects of vascular restenosis and thrombosis due to corrosion of metal. In addition, when blood vessels are regenerated, there is a risk that an additional procedure is required to remove the stent again or that a person will have to eat a thrombolytic agent for the rest of his life. In order to solve this issue, many stent manufacturers have developed drug-releasing stents by coating the stents with drugs loaded on polymers. However, the aforementioned side effects are still not significantly solved. In order to solve the fundamental issue, the need to replace metal materials with biodegradable materials has emerged.
Related art document KR10-2302544 B1 provides a biodegradable resin composition for manufacturing a stent. but does not mention that when two or more biodegradable materials are melted at a high temperature and mixed and then stent tube extrusion is performed, brittleness occurs and tube formation is impossible.
In general, in order to solve this issue, various additives such as plasticizers, antioxidants, stabilizers, and nucleating agents are used, but the use of additives is limited in the medical field.
Accordingly, the inventors of the present disclosure completed the invention

- 2 -Date Recue/Date Received 2022-11-25 by developing a method of preparing a biodegradable composite material composition capable of extruding a stent tube by mixing a biodegradable material even at a low temperature without using an additive.
Related art document Patent document (Patent Document 001) Korean Patent No. 10-2302544 B1 SUMMARY OF THE INVENTION
The present disclosure has been contrived in consideration of the above-mentioned problems in the related art, and an object of the present disclosure is to provides a method of preparing a biodegradable composite material composition for manufacturing a stent, the method including:
(1) drying polylactic acid and poly(L-lactide-co-trimethylene carbonate) for 20 to 30 hours;
(2) immersing the dried polylactic acid and poly(L-lactide-co-trimethylene carbonate) in chloroform;

(3) preparing a sol-gel by dissolving the immersed polylactic acid and poly(L-lactide-co-trimethylene carbonate) at 40 to 60 C;

(4) pulverizing the prepared sol-gel after drying; and

(5) re-drying the pulverized product of step (4).
Another object of the present disclosure is to provides a biodegradable composite material composition for manufacturing a stent prepared by the manufacturing method thereof.
To achieve the above-mentioned objects, an exemplary embodiment of the present disclosure provides a method of preparing a biodegradable composite material Date Recue/Date Received 2022-11-25 composition for manufacturing a stent, the method including:
(1) drying polylactic acid and poly(L-lactide-co-trimethylene carbonate) for 20 to 30 hours;
(2) immersing the dried polylactic acid and poly(L-lactide-co-trimethylene carbonate) in chloroform;
(3) preparing a sol-gel by dissolving the immersed polylactic acid and poly(L-lactide-co-trimethylene carbonate) at 40 to 60 C;
(4) pulverizing the prepared sol-gel after drying; and (5) re-drying the pulverized product of step (4).
Hereinafter, the present disclosure will be described in detail for each step.
The polylactic acid has excellent heat resistance and strength among biodegradable resins, and excellent transparency after molding. Polylactic acid is a polyester synthesized by polycondensation of lactic acid or ring-opening polymerization of lactide, and has intermediate physical properties between polyamide and polyethylene terephthalate (PET). Polylactic acid is sourced primarily from natural vegetable sugar components obtained from potatoes and corn, and thus has high biodegradability and generally high hardness. Polylactic acid is used for various purposes such as films, packaging containers, sheets, packaging materials, coatings, and medical materials, and is a resin that has been spotlighted as an eco-friendly plastic product instead of PE (Poly ethylene) and PVC (Polyvinyl chloride). Polylactic acid has isomers of poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), and poly-D,L-lactic acid (PDLLA), and at least one thereof may be used in the present disclosure.
The poly(L-lactide-co-trimethylene carbonate) is a copolymer prepared through a copolymerization reaction between poly-L-lactide and trimethylene carbonate, and has viscoplastic properties and is widely used as a medical material such as an Date Recue/Date Received 2022-11-25 implant material as a human-friendly polymer.
Step (1) is a step of drying polylactic acid and poly(L-lactide-co-trimethylene carbonate) for 20 to 30 hours. Through the drying, it is possible to adjust the moisture content included in polylactic acid and poly(L-lactide-co-trimethylene carbonate). In this case, a weight ratio of the prepared polylactic acid and poly(L-lactide-co-trimethylene carbonate) is preferably 4:1 to 20:1, but is not limited thereto.
Step (2) is a step of immersing the dried polylactic acid and poly(L-lactide-co-trimethylene carbonate) in chloroform, and corresponds to a preparation step for forming a sol-gel including polylactic acid and poly(L-lactide-co-trimethylene carbonate).
In this case, the polylactic acid and poly(L-lactide-co-frimethylene carbonate) dried in step (1) may be immersed in chloroform with 18 to 20 times a weight of the polylactic acid and poly(L-lactide-co-trimethylene carbonate). When the weight of chloroform is less than the above range, gelation of the mixture proceeds, and when the weight of chloroform exceeds the above range, it is difficult to secure a desired viscosity of the sol-gel.
Step (3) is a step of preparing a sol-gel by dissolving the immersed polylactic acid and poly(L-lactide-co-trimethylene carbonate) at 40 to 60 C. As the sol-gel is prepared by mixing and dissolving at a low temperature, the resin may be prepared without damage to the biodegradable polymer vulnerable to high temperature.
The dissolution in step (3) may be performed by mixing a mixture at 200 to 300 RPM, and after the sol-gel is prepared by mixing, it may be possible to obtain a sol-gel by reducing the RPM.
Step (4) is a step of pulverizing the prepared sol-gel after drying. Through the pulverization, it is possible to secure the uniformity of the biodegradable composite Date Recue/Date Received 2022-11-25 material composition for manufacturing a stent. Since an average diameter of particles according to the pulverization is directly related to the control process of a stent tube processing process, it is important to adjust the average diameter of the particles to an appropriate level through pulverization. The average diameter of the particles according to the pulverization in step (4) may be 100 gm to 3 mm.
Step (5) is a step of re-drying the pulverized product of step (4), and re-drying for a sufficient time until the desired moisture content is measured. The desired moisture content of the resin in step (5) may be 0.01 to 0.5 wt%.
Another exemplary embodiment of the present disclosure provides a biodegradable composite material composition for manufacturing a stent prepared by the aforementioned manufacturing method.
Yet another exemplary embodiment of the present disclosure provides a stent prepared from the biodegradable composite material composition for manufacturing the stent.
Another exemplary embodiment of the present disclosure provides a biodegradable composite material composition for manufacturing a stent having an average diameter of particles of 100 gm to 3 mm. The biodegradable composite material composition for manufacturing the stent includes polylactic acid, and poly(L-lactide-co-trimethylene carbonate), wherein the polylactic acid and poly(L-lactide-co-trimethylene carbonate) are dissolved in chloroform at 40 to 60 C for reaction to provide a biodegradable composite material composition for manufacturing a stent.
Terms used in the above examples are defined in the same way as the aforementioned terms unless otherwise specified.
The polylactic acid may be included in an amount of 80 to 95.3 parts by weight based on 100 parts by weight of the total polylactic acid and poly(L-lactide-co-

- 6 -Date Recue/Date Received 2022-11-25 trimethylene carbonate), and the poly(L-lactide-co-trimethylene carbonate) may be included in an amount of 4.7 to 20 parts by weight based on 100 parts by weight of the biodegradable composite material composition for manufacturing the stent, but is not limited thereto. In a preferred exemplary embodiment, the polylactic acid may be included in an amount of 85 to 95 parts by weight based on 100 parts by weight of the total polylactic acid and poly(L-lactide-co-trimethylene carbonate), and the poly(L-lactide-co-trimethylene carbonate) may be included in an amount of 5 to 15 parts by weight based on 100 parts by weight of the total polylactic acid and poly(L-lactide-co-trimethylene carbonate).
The biodegradable composite material composition for manufacturing the stent according to the exemplary embodiment of the present disclosure may be manufactured by a low-temperature sol-gel method to reduce physical and/or chemical damage to a biodegradable resin that is weak to heat, and has excellent physical properties when extruding a stent tube, thus making it easy to process.
DETAILED DESCRIPTION
Hereinafter, exemplary embodiments of the present disclosure will be described in more detail. Exemplary embodiments of the present disclosure may be modified in various forms, and the scope of the present disclosure should not be construed as being limited to the following exemplary embodiments. These exemplary embodiments are provided to more completely explain the present disclosure to those of ordinary skill in the art.
Example 1 Manufacturing of Biodegradable Composite Composition for Stent

- 7 -Date Recue/Date Received 2022-11-25 The experiment was carried out after 95 parts by weight of poly-L-lactic acid (PLLA) 5 parts by weight of poly(L-lactide-co-trimethylene carbonate) were dried in a vacuum oven at 60t for 24 hours. 95 parts by weight of the dried polylactic acid, 5 parts by weight of poly(L-lactide-co-trimethylene carbonate), and chloroform 18 times the weight of the raw material were added to a 20L jacketed reactor and mixed to conduct a reaction. Mixing was carried out at 50 C until all the raw materials were dissolved and transparent, and the RPM was maintained at 200 to 300. When the mixing was completed, the sol-gel prepared after lowering to RPM 150 was drained.
The prepared sol-gel was transferred to a tray and dried naturally at room temperature for 24 hours. Thereafter, vacuum drying was performed in a vacuum oven at 80 C for 24 hours. The dried biodegradable plastic sheet was pulverized to have a particle diameter of 100 gm to 3 mm. The pulverized biodegradable composite material composition was again vacuum dried in an oven at 80 C for 24 hours.
The dried biodegradable composite material composition was completed by checking that the moisture was included in an amount of 0.5% by weight or less through a heated moisture meter.
Example 2 In the same conditions as in Example 1, the weight ratio of the biodegradable raw material was changed to 90 parts by weight of poly-L-lactic acid (PLLA) and 10 parts by weight of poly(L-lactide-co-trimethylene carbonate) to prepare a biodegradable composite material.
Example 3 In the same conditions as in Example 1, the weight ratio of the biodegradable

- 8 -Date Recue/Date Received 2022-11-25 raw material was changed to 85 parts by weight of poly-L-lactic acid (PLLA) and 15 parts by weight of poly(L-lactide-co-trimethylene carbonate) to prepare a biodegradable composite material.
Comparative Example 1 All raw materials used were dried in a vacuum oven at 60 C for 24 hours before the experiment, and then the experiment was carried out. 95 parts by weight of poly-L-lactic acid (PLLA) for medical uses and 5 parts by weight of poly(L-lactide-co-trimethylene carbonate) were pre-mixed in a mixer to prepare a biodegradable composite material using a twin extruder at 210 C.
Comparative Example 2 In the same conditions as in Comparative Example 1, the weight ratio of the biodegradable raw material was changed to 90 parts by weight of poly-L-lactic acid (PLLA) and 10 parts by weight of poly(L-lactide-co-trimethylene carbonate) to prepare a biodegradable composite material.
Comparative Example 3 In the same conditions as in Comparative Example 1, the weight ratio of the biodegradable raw material was changed to 85 parts by weight of poly-L-lactic acid (PLLA) and 15 parts by weight of poly(L-lactide-co-trimethylene carbonate) to prepare a biodegradable composite material.
Experimental Example 1. Physical Characteristic Analysis of Resins The Tg, MP, melt index (MI), and thermal decomposition temperature of the

- 9 -Date Recue/Date Received 2022-11-25 resins of Examples 1 to 3 were measured and shown in Table 1 below.
[Table 1]
irge00 iwecp min.) temperaarer0 ExamPle 1 62. 1760 0.55. 342.
Example 2 620 176., 0.52. 3390 Example 3 174e 0.59, 3360 As a result of the investigation, the resin of Example 2 had the lowest MI
value, so it was expected that the easiest processing conditions for extrusion might be secured.
Experimental Example 2. Appearance Test of Stent Tube Made of Resin The inner diameter (ID), outer diameter (OD) and thickness (TN) of the stent tube manufactured by extruding the resins of Examples 1 to 3 under the same conditions, respectively, were measured for each position of the tube and are shown in Table 2 below. Although the resins of Comparative Examples 1 to 3 were intended to be extruded into a stent tube under the same conditions, it was impossible to manufacture a stent tube because the tube was broken due to brittleness.
[Table 2]

Date Recue/Date Received 2022-11-25 ID (mm) QD (mm) TN (mm) Average I .. 92,0 2.483 0.256 Initial stage St dant ':,.'o 5 0.023 Dga' lion Example 1 middle Average "11 6 1 9.. 2 I'5 0.184 stage sianded .027 0.003 Dev24hon Final Average 1 92. 9 2...426 0.204 stage Standard Devuttort Average 2.077 2.489 0.202 Initial stage standana 0.004 0.003 0.001 Deviation .
Example 2 Average 2.033 2.456 0.210 Middle . , -stage Standard 0.014 0.012 0.001 Deviation Final Average 2.061 , 2.456 0.200 stage Standard 0.002 0.003 0.007 Deviation , -Average 1 9E17 .2,402 , Initial ____________________________________________________ ' stage stanand noviation Average 2 , ir,,,3^01 2 4 4 9 01,0..B
Example 3 Middle , stage standafd Deviation .
Final Average 2.056 2 4e5 0.204 stage Standard 0.027 ,').,1(', 11,01 a Deviation _ r As a result of the analysis, since the tube of Example 2 was most uniform in all values of the inner diameter, outer diameter, and thickness, it was expected that the surface treatment of the tube would also be the easiest.
Experimental Example 3. Physical Property Test of Tube Made of Resin The cross-sectional area, maximum load strength, tensile strength, yield load strength, distinction distance, maximum displacement, elongation, true stress and true strain of the stent tube manufactured in Example 2 were measured and shown in Table 3 below.
[Table 3]

Date Recue/Date Received 2022-11-25 Max Textule Yveld Yteld Drat.ne Max Eking- The true Matters Vera' load strength bid strength distance &spine gym stress 'tram Onms) (N) _Wrote) (N) (tlivnere) Conold DetnO 000001/ 190 I 14f.k4 Oe 99 00 52 71 VO9 OS 2t w Example I
ite2ad'f.,..õ,thot = 5757 et 67 72 6 A, eral. 682o ,) in 76 79 go tors4 Example 2 ittltmd Q 196 66 r6 V 2Z
V
Average 4 3000 In cis 4to ;e.3 I AI
ExamPle 3 Standard Deviatwa 00 %I 0.4 1)2 179 66 As a result of the analysis, the values of all stent tubes were measured to be appropriate for processing, and in particular, the tensile strength and true strain of Example 2 were measured to remarkably match the processing conditions.
The foregoing detailed description illustrates and describes the present disclosure. Additionally, the disclosure shows and describes the preferred exemplary embodiments of the present disclosure, and it is to be understood that the present disclosure is capable of being used in various other combinations, modifications, and environments and is capable of being changed or modified within the scope of the inventive concept as expressed herein, commensurate with the above teaching and/or the skill or knowledge of the relevant art. The exemplary embodiments described hereinabove are further intended to explain best modes known of practicing the present disclosure and to enable others skilled in the art to utilize the present disclosure in such, or other, exemplary embodiments and with the various modifications required by the particular applications or uses of the present disclosure. Accordingly, the detailed description is not intended to limit the present disclosure to the exemplary embodiments described hereinabove. In addition, it is intended that the appended claims be construed to include alternative exemplary embodiments.

Date Recue/Date Received 2022-11-25

Claims (10)

WHAT IS CLAIMED IS:

1. A method of preparing a biodegradable composite material composition for manufacturing a stent, the method comprising:
(1) drying polylactic acid and poly(L-lactide-co-trimethylene carbonate) for 20 to 30 hours;
(2) immersing the dried polylactic acid and poly(L-lactide-co-trimethylene carbonate) in chloroform;
(3) preparing a sol-gel by dissolving the immersed polylactic acid and poly(L-lactide-co-trimethylene carbonate) at 40 to 60 C;
(4) pulverizing the prepared sol-gel after drying; and (5) re-drying the pulverized product of step (4).

2. The method of claim 1, wherein a weight ratio of the added polylactic acid and poly(L-lactide-co-trimethylene carbonate) is 4: 1 to 20: 1 .

3. The method of claim 1, wherein the polylactic acid and poly(L-lactide-co-trimethylene carbonate) dried in step (1) is immersed in chloroform with 18 to 20 times a weight of the polylactic acid and poly(L-lactide-co-trimethylene carbonate).

4. The method of claim 1, wherein the dissolution in step (3) is performed by mixing a mixture at 200 to 300 RPM.

5. The method of claim 1, wherein an average diameter of particles according to the pulverization in step (4) is 100 gm to 3 mm.

6. The method of claim 1, wherein a moisture content of the composition according to the re-drying in step (5) is 0.01 to 0.5 wt%.

7. A biodegradable composite material composition for manufacturing a stent prepared by the method of any one of claims 1 to 6.

8. A stent manufactured from the biodegradable composite material composition for manufacturing the stent of claim 7.

9. A biodegradable composite material composition for manufacturing a stent having an average diameter of particles of 100 gm to 3 mm, the composition comprising:
polylactic acid; and poly(L-lactide-co-trimethylene carbonate), wherein the polylactic acid and poly(L-lactide-co-trimethylene carbonate) are dissolved in chloroform at 40 to 60 C for reaction.

10. The composition of claim 9, wherein:
the polylactic acid is included in an amount of 80 to 95.3 parts by weight based on 100 parts by weight of the total polylactic acid and poly(L-lactide-co-trimethylene carbonate); and the poly(L-lactide-co-trimethylene carbonate) is included in an amount of 4.7 to 20 parts by weight based on 100 parts by weight of the biodegradable composite material composition for manufacturing the stent.