WO2013042870A1

WO2013042870A1 - Biodegradable polymer for a suture and method for manufacturing same

Info

Publication number: WO2013042870A1
Application number: PCT/KR2012/006079
Authority: WO
Inventors: 최교창; 송승호; 백두현; 지민호; 최송연; 박지희
Original assignee: 주식회사 메타바이오메드
Priority date: 2011-09-23
Filing date: 2012-07-31
Publication date: 2013-03-28
Also published as: KR101177656B1

Abstract

The present invention relates to a biodegradable polymer for a suture, and to a method for manufacturing same. The method for manufacturing a biodegradable polymer for a suture according to the present invention comprises the steps of: preparing a preliminary polymer by inputting glycolide, ε-carprolactone, and lactide into a polymerization reactor and triggering a polymerization reaction at 50-190°C for 5-7 hours, wherein said ε-carprolactone is inputted at one time, said glycolide is dividedly inputted 10 to 15 times, and said lactide is dividedly inputted 2 to 5 times; and additionally inputting glycolide into the polymerization reactor and then triggering a polymerization reaction at 200-220°C for 0.5-1.5 hours to obtain a final polymer.

Description

Biodegradable Polymer for Suture and Manufacturing Method

The present invention relates to a biodegradable polymer for suture and a method for manufacturing the same, which can replace the catgut, a natural polymer material having a high decomposition rate, and is faster than conventional poly (glycolide-co-ε-caprolactone). It relates to a method for producing a biodegradable polymer for sutures having a speed.

Biodegradable sutures can be classified into natural absorbent sutures and synthetic absorbent sutures.

Natural absorbent sutures have been used for a long time with catgut obtained from sheep intestines.

Chromium-treated catmic (chromic catgut) is widely used to retard the cataracts because it is too fast to decompose. However, since these fibers are made of heterologous proteins, they may have a weak reaction with biological tissues and a high infection rate. In addition, there is a disadvantage that the processability is also very poor compared to the synthetic fiber due to the non-uniformity of the thickness, the amount of use is gradually decreasing.

Sutures replacing such catguts include sutures based on polyglycolide (PGA, Poly (glycolide)).

In the early 1970s, American Cyanamid Inc. commercialized synthetic absorbent sutures under the name Dexon for the first time in the world using polyglycolide.In 1987, Japanese Medical Supply Corp. launched the brand name Medifit. In the case of Samyang Co., Ltd., in collaboration with KIST, the commercialization of the brand name 'Trisorb' has been commercialized since 2000 and exported.

However, polyglycolide has a high strength and a fast decomposition rate when manufactured from monofilaments, but has a disadvantage in that the rigidity is too high and stiff so that sealing and knotting are difficult.

In order to solve this drawback, polyglycolide is blended or copolymerized with a polymer having high flexibility such as polycaprolactone to prepare PGCL (Poly (glycolide-co-ε-caprolactone)) which is a copolymer of glycolide and caprolactone. This research has been made, and the related patent discloses a technique for preparing a glycolide and an epsilon -caprolactone random copolymer in claim 2 of US Pat. No. 4,700,704 (Patent Document 1).

However, such a technique has a disadvantage in that it is extremely difficult to manufacture sutures due to low orientation.

Thus, US Patent No. 4,045,418 (Patent Document 2) discloses a technique for preparing terpolymers of lactide, ε-caprolactone, and glycolide, in which case the lactide content in this technology is at least 60% or more. The very slow rate of degradation leads to limitations in use in the medical field.

* Prior art literature *

(Patent Document 1) US 4,700,704 (October 20, 1987)

(Patent Document 2) US 4,145,418 (1977.08.30)

Biodegradable polymer and manufacturing method for suture of the present invention is to solve the problems occurring in the prior art as described above, biodegradable polymer having a faster decomposition rate than the suture made of conventional PGCL copolymer while replacing the joists and It is to provide a manufacturing method.

In the method for preparing biodegradable polymer for suture of the present invention, glycolide, ε-caprolactone, and lactide are added to a polymerization reactor to prepare a prepolymer by polymerization reaction at a temperature of 50 to 190 ° C. for 5 to 7 hours. ε-caprolactone is added at a time, the glycolide is divided into 10 to 15 divided input, the lactide is divided into two to five pre-polymer preparation step; After the addition of the glycolide to the polymerization reactor in the polymerization of 0.5 to 1.5 hours at a temperature of 200 ~ 220 ℃ to produce a final polymer to produce a final polymer; comprises a.

At this time, the glycolide, ε-caprolactone, lactide in the prepolymer manufacturing step is characterized in that the input in a molar ratio of 55 ~ 65: 30 ~ 20: 15.

In addition, the glycolide, ε-caprolactone, lactide in the final polymer manufacturing step is characterized in that the molar ratio of 75: 15 ~ 18: 10 ~ 7.

In addition, the glycolide in the prepolymer manufacturing step is divided into 10 to 15 divided input, the lactide is characterized in that divided into 2 to 5 divided input.

The biodegradable polymer for suture use of the present invention is characterized in that it is prepared by any one of the above manufacturing method.

According to the present invention, a biodegradable polymer having a faster decomposition rate than a suture made of a conventional PGCL copolymer while replacing a joist is provided, and a method of manufacturing the same.

1 is a graph showing the conversion rate of each monomer according to the reaction time when glycolide, ε-caprolactone, lactide.

2 is a graph showing the relative conversion of each monomer with respect to the overall conversion of the copolymer according to FIG.

3 is a graph showing the average block length of the prepolymer according to the composition ratio of ε-caprolactone and lactide.

4 is a graph showing the average block length of the final polymer according to the composition ratio of ε-caprolactone and lactide.

Figure 5 is a graph showing the pH change of the final polymer with decomposition time.

6 is a graph showing the weight change rate of the final polymer according to the decomposition time.

Figure 7 is a view showing the shape change with decomposition time.

Prior to the description of the method for producing the biodegradable polymer for suture use of the present invention, the raw material of the present invention will be briefly described.

Glycolide used in the present invention has a structure as shown in Formula 1 below, the melting point is 75 ℃, the molar mass is 116.07g / mol.

Formula 1

Caprolactone (ε-Caprolactone) used in the present invention has a structure as shown in Formula 2 below, the melting point is -1 ℃, the boiling point is 253 ℃, the molar mass is 114.14 g / mol.

Formula 2

Lactide (L-Lactide) used in the present invention has a structure as shown in Formula 3 below, the melting point is 95 ~ 97 ℃, the molar mass is 144.13g / mol.

Formula 3

Hereinafter, a method for preparing a biodegradable polymer for suture use of the present invention will be described.

The biodegradable polymer production method of suture using the present invention is largely divided into a prepolymer production step and a final polymer production step.

1. Prepolymer Preparation

Glycolide, ε-caprolactone, lactide was added to the polymerization reactor to prepare a prepolymer by polymerization reaction at a temperature of 50 ~ 190 ℃ for 5 to 7 hours.

At this time, the ε-caprolactone is added to the polymerization reactor once, the glycolide is divided into 10 to 15 divided into the polymerization reactor, the lactide is divided into 2 to 5 divided into the polymerization reactor.

At this time, the most preferred number of dividing glycolide is preferably 10 to 15 divisions, and in the case of lactide, 2 to 5 divisions are most preferable.

In addition, the glycolide, ε-caprolactone, lactide in the prepolymer manufacturing step is preferably added in a molar ratio of 55 ~ 65: 30 ~ 20: 15.

Formula 4 below shows an embodiment of a polymerization reaction using the ring-opening reaction of glycolide, ε-caprolactone, lactide when preparing the prepolymer.

Formula 4

(Wherein X, Y and Z are integers of 1 or more)

2. Preparation of Final Polymer

After additionally adding glycolide to the polymerization reactor, the final polymer is prepared by polymerization reaction at a temperature of 200 to 220 ° C. for 0.5 to 1.5 hours.

At this time, the glycolide in the preparation step of the final polymer, ε-caprolactone, lactide is preferably added to the glycolide so that the molar ratio of 75: 15 ~ 18: 10 ~ 7.

That is, after glycolide is added to the polymerization reactor after the prepolymer production step, the final molar ratio in preparing the final polymer is the molar ratio.

Formula 5 below shows one embodiment of the formula of the biodegradable polymer of the present invention prepared after the final polymerization.

Formula 5

(In Formula 2, X, Y, Z, n, m, p are integers of 1 or more.)

Referring to the reason for the divided input of glycolide and lactide as described above in the present invention.

In order to analyze the reactivity of each monomer, the inventor of the present invention puts the same composition ratio of each monomer into the reactor, and then conducts polymerization for 20 hours, takes a sample for 1 to 2 hours, according to ¹ H-NMR according to the reaction time. Reactivity was analyzed through the analysis.

As a result, at the beginning of the reaction, unreacted monomers were identified. After 1 hour, unreacted monomers of glycolide and lactide were present, and the peak of the glycolide region was grown the most.

On the other hand, the unreacted content of ε-caprolactone was present even after 10 hours.

Through this, it was confirmed that the order of monomer reactivity was glycolide> lactide> ε-caprolactone.

The conversion rate according to the reaction time of each monomer based on the ¹ H-NMR analysis results is shown in FIG. 1, and FIG. 2 shows the relative ratios of the unreacted monomers and the converted monomers based on this.

As shown, the glycolide monomer has a very fast reaction rate compared to ε-caprolactone and lactide monomers, and it can be seen that polymerization takes place at the initial stage of the reaction.

On the other hand, ε-caprolactone has the slowest reaction rate, and lactide has a moderate reactivity between glycolide and ε-caprolactone.

After 3 hours, most of the glycolide monomer was polymerized, whereas ε-caprolactone had a conversion rate of about 60% and most reactions were not completed until 14 hours.

On the other hand, lactide shows a conversion rate of about 90% after 3 hours, but since the small amount of unreacted monomer exists after 20 hours of reaction, it can be confirmed that the conversion rate does not reach 100%.

As such, when the reaction rate of each monomer is different from each other, when the monomer is added at a time, the glycolide reacts at a high speed, whereas ε-caprolactone is not introduced into the copolymer and exists as an unreacted monomer.

These unreacted monomers eventually need to be removed because they lower the copolymer's physical properties and degrade process capability.

That is, in the present invention, the monomers are divided as described above according to various experimental results for reducing the content of unreacted monomers and producing a more random polymer.

On the other hand, the inventors of the present invention investigated the composition and chemical structure of the prepolymer according to the number of divided doses of lactide, as shown in Table 1 below.

Table 1

Analysis of Composition and Viscosity of Prepolymer with Lactide Split Injection

LA split injection		Creation costs	Average block length			Viscosity (IV)
system	Temperature (℃)	Gp / Cp / Lp / Gm / Cm / Lm	L _GG	L _C	L _LL	Viscosity (IV)
1 split	50	55.6 / 24.7 / 16.4 / 0.4 / 2.2 / 0.6	2.09	1.12	3.50	0.956
2 split	50/120	55.2 / 25.5 / 16.5 / 0.3 / 1.8 / 0.7	2.40	1.14	2.88	1.008
3 divisions	50/120/190	54.3 / 28.4 / 15.5 / 0.3 / 0.9 / 0.6	2.33	1.14	2.59	1.012

(ε-caprolactone and lactide in a 2: 1 molar ratio, Gp: glycolide polymer, Cp: ε-caprolactone polymer, Lp: lactide polymer, Gm: glycolide monomer, Cm: ε-caprolactone monomer , Lm: lactide monomer, L _GG : glycolide block length, L _C : ε-caprolactone block length, L _LL : lactide block length)

As shown in the drawing, as the number of lactide fractions increases, the content of unreacted monomers of ε-caprolactone decreases.

It can also be seen that the block length of lactide is also shorter and the viscosity is increased.

Therefore, lactide is preferably divided into two to five as shown.

On the other hand, the biodegradable polymer of the suture of the present invention configured as described above is relatively lactide and ε- due to the decomposition of glycolide during the initial stage of degradation, that is, during the first week, when the monomer content changes according to the decomposition time of the final polymer. The relative content of caprolactone is increased, and the content of ε-caprolactone is relatively increased as the content of glycolide and lactide decreases after 1 to 2 weeks of decomposition.

After 3 weeks of decomposition, the relative content of glycolide increases again, and the relative content of lactide and ε-caprolactone decreases again.

This is because the decrease in the content of glycolide in the early stage of decomposition is due to the fact that the glycolide amorphous region is easily decomposed due to the easy penetration of water, and in fact, the decomposition rate is glycolide amorphous region-> lactide amorphous region-> ε-caprolactone amorphous. This is because the region proceeds in the order of the region of glycolide crystals.

In this process, since lactide has a faster decomposition rate than ε-caprolactone, the decomposition rate is much faster than that of the conventional PGCL copolymer.

On the other hand, since the CGC sequence has a strong resistance to hydrolysis, the decomposition does not occur well, so the smaller the content of the CGC sequence is advantageous to the decomposition.

In general, the CGC sequence is generated by a second transesterification reaction in which ε-caprolactone is activated by a catalyst to attack the glycolide unit. In the present invention, the content of ε-caprolactone is relatively reduced due to the introduction of lactide. By lowering the frequency of the CGC transesterification reaction to reduce the content of CGC compared to the conventional PGCL, it shows a fast decomposition rate.

Hereinafter, an embodiment of the present invention will be described.

1. Preparation of biodegradable polymer for suture 1

Glycolide, ε-caprolactone, and lactide were added to the reactor.

At this time, the molar ratio of glycolide, ε-caprolactone, and lactide was set to 55: 36: 9.

DEG, an initiator, has a structure as shown in Chemical Formula 6 below, a melting point of -10.45 ° C, a boiling point of 253 ° C, and a molar mass of 106.12 g / mol.

Stannous octoate, a catalyst, has a structure as shown in Formula 7 below, and has a molar mass of 405.1 g / mol.

Formula 6

Formula 7

The total amount of ε-caprolactone was initially added, the glycolide was divided into 10 portions, and the lactide was divided into 5 portions.

The temperature condition of the reactor was taken to maintain the temperature increase to 50 ~ 190 ℃.

After preparing the prepolymer through the above process, the glycolide was added and maintained for 1 hour while maintaining the temperature condition of the reactor at 198 ℃.

Glycolide, caprolactone and lactide were added to the final addition of glycolide to 75: 20: 5 based on the molar ratio.

Hereinafter, an experimental example of the polymer prepared by the method of manufacturing a biodegradable polymer for suture according to the present invention will be described.

1. Composition and chemical structure of prepolymer and final polymer

In order to determine the chemical structures of the prepolymer and the final polymer in the production method according to Example 1, the change in the chain structure of each copolymer was confirmed through ¹ H-NMR analysis.

TABLE 2

Composition and average block length of prepolymer and final polymer, PGCL

Furtherance	Average block length
Furtherance	L _GG	L _C	L _LL
Prepolymer	2.05	1.20	2.40
Final polymer	3.82	1.20	2.42

Table 2 shows the average block length of each monomer in the prepolymer and the final polymer in the above examples.

On the other hand, Figure 3, but proceeded as in Example 1, ε- caprolactone: lactide experiment by varying the ratio of the composition is shown in the graph the average block length of the prepolymer accordingly.

As shown, as the content of lactide increases, the average block length of glycolide and lactide of the prepolymer increases, and the block length of ε-caprolactone remains constant.

As the content of lactide increases, the block length of lactide increases, and ε-caprolactone, which has a relatively low content, is activated by a catalyst, thereby decreasing the probability of attacking glycolide and lactide. The block length of lactide is increased.

The monomer average block length of the final polymer obtained by additional addition of glycolide after the prepolymer synthesis is completed is shown in FIG. 4.

If we check the chemical structure of the final polymer, it can be observed that the tendency is very similar to that of the prepolymer depending on the content of ε-caprolactone and lactide.

In the prepolymer stage, which is a one-step reaction, the average block length of ε-caprolactone and lactide determined at the beginning of the reaction is almost unchanged over the entire reaction, but is the product of terminal esterification by the activated caproyl and lactidyl sequences. It induces a -CGC- or -LGL- sequence, which greatly affects the average block length of glycolide.

In addition, in the two-step reaction, since the homomonomer growth reaction mainly occurs by glycolide, the average block length of ε-caprolactone and lactide determined in the prepolymer reaction step is almost unchanged.

This indicates that the final polymer was prepared in the form of an ABA block copolymer.

Therefore, the most important factor that determines the chemical structure of the final polymer is the chemical structure of the prepolymer prepared in step 1.

2. Decomposition behavior test of final polymer

The final polymer sample of Example 1 was immersed in phosphate buffer solution (PBS) of pH 7.4 and the pH of the PBS solution was examined using a pH meter (ISTEK) over time.

At this time, as a comparative example, the PGCL was examined as a comparison target, and the results are shown in FIG. 5.

In addition, the weight reduction of the final polymer due to decomposition is calculated by subtracting the weight of the sample after decomposition by subtracting the weight of the sample after decomposition and dividing by the weight of the sample before decomposition to calculate the percentage reduction.

At this time, PGCL was also compared as a comparative example.

As shown, the final polymer prepared by the production method of the present invention can be seen that it maintains a certain strength at the initial stage of decomposition and then decreases rapidly after a certain period of time.

That is, the polymer according to the present invention shows a similar decomposition behavior initially with the PGCL copolymer, but it can be seen that it decomposes at a faster rate after a certain period of time.

3. Experiment of shape change by decomposition

7 is a view showing an image observed by the FE-SEM decomposition of the final polymer sample of Example 1 with time at a temperature of ℃.

In the table of the figure, the PCGL on the left is the above-described PGCL, and the PCGLA on the right is a product manufactured according to Example 1 of the present invention.

As shown in the figure, it can be seen that the phenomenon of the surface cracking of the final polymer produced by the present invention occurs more quickly than the existing product.

In other words, the decomposition behavior of the product of Example 1 occurs much faster.

As described above, in the present invention, the glycolide, ε-caprolactone, and lactide are divided into two stages and subjected to a polymerization reaction, and the glycolide and lactide are separately divided and introduced into the preparation process.

In this case, the chemical structures of the prepolymer and the final polymer showed that the average block length of the lactide and the average block length of the ε-caprolactone were almost unchanged. To a block copolymer of ABA type.

After this process, the final polymer has a much faster decomposition rate than conventional PGCL.

The method of producing biodegradable polymer for suture use of the present invention is not limited to the production of suture, and may be applied to the preparation of various biodegradable polymers applied to various surgical procedures.

Claims

In the method for producing a biodegradable polymer for suture,

Glycolide, ε-caprolactone, lactide was added to the polymerization reactor at a molar ratio of 55 to 65: 30 to 20: 15 to polymerize for 5 to 7 hours at a temperature of 50 to 190 ℃ to prepare a prepolymer, ε-caprolactone is added at a time, the glycolide is divided into 10 to 15 divided doses, the lactide is divided into three divided doses, the input time is made at a temperature of 50 ℃, 120 ℃, 190 ℃ Preparing a prepolymer;

Glycolide was added to the polymerization reactor such that glycolide, ε-caprolactone, and lactide were 75: 15 to 18: 10 to 7, and then polymerization reaction was performed at a temperature of 200 to 220 ° C for 0.5 to 1.5 hours. Configured to include a final polymer manufacturing step of preparing a final polymer,

Method for producing biodegradable polymer for suture.
In the suture polymer,

It is manufactured by the manufacturing method of claim 1,

Formula is

X, Y, Z, n, m, p is an integer of 1 or more, characterized in that

Biodegradable polymer for sutures.