JP2009132769A - LACTIDE/epsilon-CAPROLACTONE COPOLYMER FOR MEDICAL IMPLANT - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a flexible lactide/ε-caprolactone copolymer for medical implants that is very highly safe as no higher alcohols are contained therein and is useful for preparing medical implants requiring flexibility such as an artificial dura, an artificial blood vessel and the like. <P>SOLUTION: The lactide/ε-caprolactone copolymer for medical implants is a copolymer of a lactide and ε-caprolactone, where the copolymer has the molar ratio of the lactide and ε-caprolactone (lactide/ε-caprolactone) of 40/60-60/40 and a weight-average molecular weight of 100,000-500,000, contains no higher alcohol components and has a melt enthalpy, resulting from a crystal formed when it is heat-melted into a molded item, of at most 10 J/g. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to a flexible lactide for medical implants that is extremely safe and does not contain higher alcohols, and is useful for producing medical implants that require flexibility such as artificial dura mater and artificial blood vessels. It relates to an ε-caprolactone copolymer.

In recent years, biodegradable absorbable polymers such as polylactide have been increasingly used as medical implants made of polymer materials. Biodegradable absorbable polymer gradually loses its shape due to hydrolysis, so there is no need to remove it by re-surgery like conventional non-degradable medical implants, greatly reducing the burden on patients. can do.

Examples of the biodegradable absorbable polymer include, for example, aliphatic ethers such as polyglycolide, polylactide, polycaprolactone, polyvalerolactone, and polyester ethers (poly-1,4-dioxanon-2-one, poly1, 5-dioxepane-2-one, ethylene glycol-copolymer of the above aliphatic polyester), a copolymer of the above aliphatic polyester and polyester ether, amino acid, hyaluronic acid, alginic acid, cellulose oxide and the like. Among these, a copolymer of lactide and ε-caprolactone is relatively excellent in flexibility, and thus has attracted attention as a material for medical implants that require flexibility such as an artificial dura mater and an artificial blood vessel (for example, Patent Document 1).

However, the copolymer of lactide and ε-caprolactone has a high flexibility immediately after polymerization, but gradually loses its flexibility as it is left untreated (hereinafter referred to as “self”). Also called “curing”). In particular, in order to mold as a medical implant, the molded body is usually formed by heating and melting, but the flexibility is remarkably lost after heating and melting.

Patent Document 2 describes a bioabsorbable polymer composed of a copolymer of lactide and ε-caprolactone that hardly undergoes self-curing. The invention described in Patent Document 2 is to make self-curing difficult to proceed by adjusting the average chain length of lactide and ε-caprolactone in the copolymer, and the average chain length is determined when the copolymer is produced. It is described that it is adjusted according to the reaction temperature and that the average chain length is such that self-curing is most difficult to proceed when the reaction temperature is about 140 ° C.

However, in Patent Document 2, an experiment is conducted on the premise that a higher alcohol is used as a polymerization initiator at the time of polymerization of a copolymer of lactide and ε-caprolactone. Since it remains after being modified, there is a problem that it must be used for a medical implant.
JP-T 6-501045 JP 2005-306999 A

The present invention relates to a flexible lactide for medical implants that is extremely safe and does not contain higher alcohols, and is useful for producing medical implants that require flexibility such as artificial dura mater and artificial blood vessels. An object is to provide an ε-caprolactone copolymer.

The present invention relates to a copolymer of lactide and ε-caprolactone for use in medical implant applications, wherein the molar ratio of lactide to ε-caprolactone (lactide / ε-caprolactone) is 40/60 to 60/40. The medical treatment has a weight average molecular weight of 100,000 to 500,000 or less, does not contain a higher alcohol component, and has a melting enthalpy of 10 J / g or less derived from crystals when heated and melted to form a molded product. It is a lactide / ε-caprolactone copolymer for medical use.
The present invention is described in detail below.

In polymerization of a copolymer of lactide and ε-caprolactone, in order to obtain a copolymer having a high degree of polymerization while avoiding uneven polymerization due to a difference in reactivity between lactide and ε-caprolactone, It was technical common sense that it was essential to add higher alcohols. However, as a result of intensive studies by the present inventors, it has been found that when a copolymerization reaction is performed at a high temperature exceeding 130 ° C., a copolymer having a sufficient degree of polymerization can be obtained without using a higher alcohol as a polymerization initiator. I found it. A copolymer obtained by reacting at a high temperature exceeding 130 ° C. without using a higher alcohol as a polymerization initiator does not contain a higher alcohol, so that it has high safety, After that, it was found that high flexibility was exhibited without self-curing, and the present invention was completed.

The lactide / ε-caprolactone copolymer for medical implants of the present invention (hereinafter also simply referred to as “copolymer”) is a copolymer of lactide and ε-caprolactone.
In the copolymer of the present invention, the molar ratio of lactide to ε-caprolactone (lactide / ε-caprolactone) is 40/60 to 60/40. When the molar ratio of lactide or ε-caprolactone is higher than 60 mol%, the crystallinity becomes high and the composition becomes hard and cannot be used for a medical implant that requires flexibility such as an artificial dura mater or an artificial blood vessel. More preferably, it is 45 / 55-55 / 45.

The copolymer of the present invention has a lower limit of the weight average molecular weight of 100,000, an upper limit of 500,000, and a molded body (medical implant) having sufficient strength when it is less than 100,000. If it exceeds 500,000, the melt viscosity is high and the moldability is poor. A preferred lower limit is 150,000 and a preferred upper limit is 450,000.

The copolymer of the present invention does not contain a higher alcohol component. When a higher alcohol component is contained, depending on the concentration, there is a concern about the influence on the human body, making it difficult to use as a medical implant.

The copolymer of the present invention has a melting enthalpy derived from a crystal of 10 J / g or less when heated and melted to form a molded body. If it exceeds 10 J / g, the crystallinity becomes high and hard, and problems such as damage to the soft tissue due to compliance mismatching such as inability to follow the deformation and expansion / contraction of the soft tissue, and inflammation may occur. And cannot be used for medical implants that require flexibility such as artificial blood vessels.

In the present specification, the melting enthalpy derived from the crystal means the calorie per unit weight observed when the biodegradable polymer is measured with a differential scanning calorimeter (DSC). Mean value. It can be said that the higher the melting enthalpy value, the higher the crystallinity.
The copolymer of lactide and ε-caprolactone can have a melting enthalpy of 10 J / g or less, that is, a low crystalline state relatively easily immediately after polymerization. However, in order to produce a medical implant using the copolymer, it is necessary to form it by heating and melting. In the conventional copolymer of lactide and ε-caprolactone, the melting enthalpy derived from the crystal is remarkably increased (that is, crystallized) through such a processing step, and the flexibility is lost.
The copolymer of the present invention is characterized in that the melting enthalpy derived from the crystals after passing through the heating and melting step is 10 J / g or less, that is, the change in melting enthalpy derived from the crystals is extremely small.

In the method for producing a copolymer of the present invention, during the copolymerization of a conventionally known lactide and ε-caprolactone, 1) a higher alcohol is not added as a polymerization initiator, and 2) the polymerization temperature exceeds 130 ° C. It is important to.
By not adding a higher alcohol, it is possible to ensure that the resulting copolymer does not contain a higher alcohol component. In the conventional technical common sense, higher alcohol was considered as an essential component, but no inconvenience occurs when the reaction temperature is set to a temperature exceeding 130 ° C. Furthermore, by setting the reaction temperature to a temperature exceeding 130 ° C., it is possible to obtain a resin with a very small change in melting enthalpy derived from crystals. A preferred lower limit is 135 ° C. The upper limit of the reaction temperature is not particularly limited, but the preferable upper limit is 170 ° C. If it exceeds 170 ° C., undesirable properties such as coloring may appear in the resulting copolymer.

Lactide and ε-caprolactone differ greatly in activation energy required for ring opening, and lactide has lower activation energy required for ring opening than ε-caprolactone. That is, as the polymerization is performed at a lower temperature, the lactide is polymerized first, the lactide chain length is increased, and the crystallinity is increased. On the other hand, the higher the polymerization temperature, the shorter the chain length of lactide and ε-caprolactone, and the monomers are randomly arranged in the molecular chain, so that the crystallinity can be lowered. By setting the reaction temperature to a temperature exceeding 130 ° C., the crystallinity of the resulting copolymer can be lowered, and crystallization can be prevented from progressing greatly even after a processing step such as heating and melting.
A method for producing a lactide / ε-caprolactone copolymer for medical implants in which a higher alcohol is not added as a polymerization initiator and the reaction temperature is higher than 130 ° C. is also one aspect of the present invention.

In the copolymerization of lactide and ε-caprolactone, an organometallic compound such as tin, zinc, iron, nickel, aluminum, potassium, sodium, titanium, antimony, bismuth, or a salt thereof may be used as a polymerization catalyst. Among these, a tin compound is preferable from the viewpoint of actual use and easy handling during polymerization, and tin octylate is more preferable from the viewpoint of reaction rate and stability.

In order to use for medical implants, it is preferable not to contain metal compounds harmful to the human body as much as possible. For example, tin octylate is known to have a relatively low toxicity to living organisms, but the effect is considered to be extremely small if it is particularly less than 1 ppm.
When a polymerization catalyst is used in the copolymerization of lactide and ε-caprolactone, it is preferable to remove the metal catalyst from the copolymer after polymerization.

The method for removing the metal catalyst is not particularly limited. For example, a method using a catalyst remover is simple and effective.
As the catalyst removing agent, those composed of an organic acid and an alcohol are preferable, and among them, those composed of acetic acid as an organic acid and isopropanol as an alcohol are preferable from the viewpoint of safety and ease of recovery. . Here, the composition ratio between the organic acid and the alcohol is such that the higher the ratio of the organic acid within the range in which the copolymer is not dissolved, the more effective catalyst removal is possible.
Specifically, for example, an acetic acid / isopropanol = 15/85 to 35/65 (volume ratio) is preferable. If the concentration of acetic acid is less than 15% by volume, the catalyst may not be removed to 1 ppm or less, and if it exceeds 35% by volume, the copolymer may be dissolved and recovery may be difficult.

The copolymer of the present invention can be processed into various shapes such as a sheet, a foam and a fibrous body by heating and melting, and the flexibility is hardly lost even after such processing steps. Moreover, it is extremely safe without containing higher alcohols.

The copolymer of the present invention is suitable for producing a medical implant that requires flexibility such as an artificial dura mater and an artificial blood vessel. The medical implant using the lactide / ε-caprolactone copolymer for medical implant of the present invention is also one aspect of the present invention.
Examples of the form of the medical implant of the present invention include a film, a sheet, a foam, a fiber structure, a molded product, or a composite thereof.
The medical implant of the present invention includes, in addition to an artificial dura mater and an artificial blood vessel, a suture thread, a bone bonding material, a fracture fixing material, a tissue filling material, a tissue reinforcing material, a tissue covering material, a tissue regeneration base material, a tissue It is also suitable as a prosthetic material, an adhesion prevention material, an artificial valve, a stent, a clip, a fiber cloth, a hemostatic material, an adhesive, a coating agent, and the like.

According to the present invention, for a flexible medical implant that does not contain a higher alcohol and is extremely safe and useful for producing a medical implant that requires flexibility such as an artificial dura mater or an artificial blood vessel. A lactide / ε-caprolactone copolymer can be provided.

Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1
1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin octylate (78 ppm in terms of tin) were placed in a separable flask and polymerized at 135 ° C. for 7 days in a nitrogen atmosphere after decompression.
The obtained copolymer was treated with a catalyst remover (acetic acid / isopropanol = 30/70 v / v) and dried under vacuum at 40 ° C. to obtain a lactide / ε-caprolactone copolymer.

The obtained lactide / ε-caprolactone copolymer was melt-molded by an extruder to form a sheet having a thickness of 100 μm and further heat-treated at 70 ° C. for 12 hours under vacuum to obtain a sheet.

(Example 2)
1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin 2-ethylhexanoate (78 ppm in terms of tin) were placed in a separable flask and polymerized at 140 ° C. for 7 days in a nitrogen atmosphere after decompression.
The obtained copolymer was treated with an isopropanol solution of acetic acid (acetic acid / isopropanol = 20/80 v / v) and dried under vacuum at 40 ° C. to obtain a lactide / ε-caprolactone copolymer.
A sheet was obtained in the same manner as in Example 1 except that the obtained lactide / ε-caprolactone copolymer was used.

(Comparative Example 1)
1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin 2-ethylhexanoate (78 ppm in terms of tin) were placed in a separable flask and polymerized at 130 ° C. for 7 days in a nitrogen atmosphere after decompression.
The obtained copolymer was treated with an isopropanol solution of acetic acid (acetic acid / isopropanol = 30/70 v / v) and dried under vacuum at 40 ° C. to obtain a lactide / ε-caprolactone copolymer.
A sheet was obtained in the same manner as in Example 1 except that the obtained lactide / ε-caprolactone copolymer was used.

(Evaluation)
The lactide / ε-caprolactone copolymers and sheets obtained in Examples 1 and 2 and Comparative Example 1 were evaluated by the following methods.
The results are shown in Table 1.

(1) Measurement of weight average molecular weight

The weight average molecular weights of the copolymer immediately after polymerization and the catalyst immediately after removal of the catalyst and the sheet immediately after molding were measured by gel permeation chromatography (GPC) using chloroform (elution rate 1 ml / min) as an eluent. The calculated molecular weight was determined as a reference substance.

(2) Measurement of melting enthalpy Immediately after polymerization, about the melting enthalpy of the copolymer immediately after removal of the catalyst and the sheet immediately after molding, DSC measurement (temperature increase rate 10 ° C./min) was performed to measure the melting enthalpy derived from the crystal part. .

(3) Measurement of the amount of residual catalyst Immediately after polymerization, the amount of catalyst remaining in the copolymer immediately after removal of the catalyst and the sheet immediately after molding was measured by IPC emission spectroscopic analysis.

表１より、実施例１、２で製造した共重合体では、重合直後、触媒除直後及びシート加工直後に測定した融解エンタルピーの変化が小さく、シート加工直後であっても１０Ｊ／ｇ以下であった。一方、比較例１で製造した共重合体では、重合後及び触媒除去後の融解エンタルピーは１０Ｊ／ｇ以下であるものの、シート加工後には融解エンタルピーが１０Ｊ／ｇを超えて大きくなった。

From Table 1, in the copolymers produced in Examples 1 and 2, the change in melting enthalpy measured immediately after polymerization, immediately after removal of the catalyst and immediately after sheet processing was small, and it was 10 J / g or less even immediately after sheet processing. It was. On the other hand, in the copolymer produced in Comparative Example 1, although the melting enthalpy after polymerization and after removal of the catalyst was 10 J / g or less, the melting enthalpy increased beyond 10 J / g after sheet processing.

According to the present invention, for a flexible medical implant that does not contain a higher alcohol and is extremely safe and useful for producing a medical implant that requires flexibility such as an artificial dura mater or an artificial blood vessel. A lactide / ε-caprolactone copolymer can be provided.

Claims (4)

A copolymer of lactide and ε-caprolactone for use in medical implant applications,
The molar ratio of lactide to ε-caprolactone (lactide / ε-caprolactone) is 40/60 to 60/40, the weight average molecular weight is 100,000 to 500,000 or less, and does not contain a higher alcohol component,
A lactide / ε-caprolactone copolymer for medical implants, wherein the melting enthalpy derived from crystals when heated and melted to form a molded product is 10 J / g or less. A medical implant comprising the lactide / ε-caprolactone copolymer for medical implants according to claim 1. The medical implant according to claim 2, wherein the form is a film, a sheet, a foam, a fiber structure, a molded product, or a composite thereof. A method for producing a lactide / ε-caprolactone copolymer for medical implants, characterized in that a higher alcohol is not added as a polymerization initiator and the reaction temperature is higher than 130 ° C.