JP4953052B2 - Anti-adhesion film - Google Patents

Description

  The present invention relates to an adhesion preventing film for preventing adhesion between living tissues.

  In the clinical field, in order to prevent adhesion of living tissue, an anti-adhesion film that physically isolates an affected area and its surrounding tissue is used. The adhesion preventing film is preferably a film having moderate flexibility and exhibiting the effect during a period when the adhesion preventing effect is necessary, and then being decomposed and absorbed in vivo.

  Currently, for example, a film made of oxidized regenerated cellulose and a film made of a hyaluronic acid / carboxymethyl cellulose mixture have been put to practical use as anti-adhesion films. However, since these materials are naturally derived, there is a risk that the quality is unstable or the risk of virus infection cannot be completely eliminated. In addition, these materials are rapidly decomposed and absorbed in a living body, and tend to be in a gel form and easily flow when contacted with a body fluid. For this reason, anti-adhesion films using such materials have been used in fields such as obstetrics and gynecology and abdominal surgery that are effective even for short-term (for example, about one week) anti-adhesion effects. It may not be suitable if a block from surrounding tissue is required over a period of time (eg, about 2 weeks or more).

In order to solve such problems, in recent years, a film made of a polymer or copolymer such as lactic acid, lactide, caprolactone, which is excellent in biocompatibility and bioabsorbability, has been proposed as an anti-adhesion film (for example, (See Patent Document 1 and Patent Document 2). A method for producing a medical product from a lactide-caprolactone copolymer has also been proposed (see Patent Document 3).
Japanese Examined Patent Publication No. 64-2383 JP 2000-189509 A Japanese Patent No. 3161729

  However, the present inventors newly paid attention to the fact that the lactide-caprolactone copolymer film has the following problems although it exhibits an appropriate decomposition and absorption rate. As a film having the most flexibility, a lactide-caprolactone copolymer film having a molar ratio of lactide to caprolactone of 50:50 is known. However, although such a film has excellent flexibility and is easy to rub against the affected area, for example, when it is rubbed against a tendon and inserted into a living body, a crack is generated within about 3 weeks, thereby It was found that the surrounding tissue invaded from the crack, and the tendon and the surrounding tissue were adhered to each other, so that a sufficient adhesion preventing effect could not be obtained. In particular, since the affected part such as a tendon takes time to heal, for example, it is necessary to isolate it from surrounding tissues for about 3 weeks to prevent adhesion, but it is sufficient if cracks occur within the above period. Can not be treated properly.

  Then, the objective of this invention is providing the adhesion prevention film which has moderate softness | flexibility and can prevent generation | occurrence | production of the crack at the time of use.

  The anti-adhesion film of the present invention is a film containing a copolymer of lactide and caprolactone, wherein the molar ratio of lactide to caprolactone in the copolymer is in the range of 65:35 to 80:20. And

  According to the anti-adhesion film of the present invention, by setting the molar ratio of lactide and caprolactone within the above range, for example, when used in a curved state in the living body or wound around the affected area, etc. Even if physical force is sometimes applied to the film, the following effects can be obtained. That is, the adhesion preventing function is exhibited without cracking for a sufficient period, and after the period has elapsed, it can be decomposed and absorbed in the living body. For this reason, it is extremely useful as an anti-adhesion film that is wound around an affected area such as a tendon. In this way, even in the case of a conventional anti-adhesion film having excellent flexibility, for example, when it is used after being bent or wound, the fact that cracks occur and a sufficient anti-adhesion effect cannot be obtained, This is the problem that the present inventors have found and focused on for the first time.

  As described above, the present invention is an adhesion-preventing film containing a copolymer of lactide and caprolactone, wherein the molar ratio (A: B) of lactide (A) to caprolactone (B) in the copolymer is The range is from 65:35 to 80:20. When the ratio of caprolactone (B) is larger than that of 65:35 (the ratio of lactide (A) is small), the molar ratio (A: B) is embedded in the living body in a curved state, for example. In this case, cracking occurs before the anti-adhesion effect for a sufficient period of time, and if the ratio of caprolactone (B) becomes smaller than that of 80:20 (the ratio of lactide (A) increases), for example, flexibility Therefore, there is a possibility that a problem that winding itself around a tendon or the like is impossible is caused. The molar ratio (A: B) is preferably 70:30 to 80:20, and preferably 75:25.

  The weight average molecular weight of the copolymer is not particularly limited, but is, for example, 100,000 to 1,500,000, preferably 200,000 to 1,000,000, and more preferably 400,000 to 800,000. When the weight average molecular weight is 100,000 or more, the film strength is further improved, and when the weight average molecular weight is 1.5 million or less, the synthesis of the copolymer is further facilitated.

  The copolymer in the present invention may be, for example, a random polymer or a block polymer. In addition, these copolymers can be used by mixing two or more kinds of copolymers having different molar ratios as long as the molar ratio is satisfied. In addition, the adhesion prevention film in this invention may contain only the copolymer of the said molar ratio, and may also contain another polymer and copolymer in the range which does not affect this invention.

  The method for preparing the copolymer in the present invention is not particularly limited, and a conventionally known method can be used. In general, lactide and caprolactone may be used as starting materials and copolymerized by ring-opening polymerization, or lactide (a cyclic dimer of lactic acid) may be synthesized from lactic acid and co-polymerized with caprolactone. It may be polymerized. The polymerization temperature of lactide and caprolactone is not particularly limited, but is preferably, for example, 150 to 170 ° C. because the resulting film is excellent in flexibility. The method for synthesizing lactide using lactic acid is not particularly limited, and a conventionally known method can be used.

  The lactide is not particularly limited, and L-lactide, D-lactide and a mixture thereof (D, L-lactide) can be used, and lactic acid includes L-lactic acid, D-lactic acid and a mixture thereof ( D, L-lactic acid) can be used. Thus, when lactic acid is used as a starting material, in the copolymer of the present invention, monomeric lactic acid is converted to dimeric lactide, and the molar ratio of converted lactide to caprolactone is within the above range. Just fill it.

  Examples of caprolactone include ε-caprolactone, γ-caprolactone, and δ-caprolactone, and among them, ε-caprolactone is preferable.

  The average chain length which is a repeating unit of lactide in the copolymer is, for example, preferably 10 or less, more preferably 6 or less. This “average chain length, which is a repeating unit of lactide in a copolymer” means the average number of molecules in which lactide (two molecules of lactic acid) that have been ring-opened during the formation of the copolymer is continuously bonded. . If the average chain length of the lactide is 10 or less, for example, the resulting film is more flexible and easy to wind. Such a copolymer can be obtained, for example, by setting the polymerization temperature high. Specifically, by setting the polymerization temperature relatively high, the degree of polymerization can be set relatively small. Can do. As a specific example, the polymerization temperature is preferably 150 to 170 ° C., for example.

  The thickness of the adhesion preventing film of the present invention is not particularly limited, but is preferably in the range of, for example, 50 to 300 μm, more preferably 100 to 200 μm, and particularly preferably 100 to 150 μm. If the thickness is 50 μm or more, the strength is further improved, and if it is 300 μm or less, the flexibility is further improved, so that the wound to the affected part is easy.

  The production method of the anti-adhesion film of the present invention is not particularly limited, and can be produced by a conventionally known film formation method such as an extrusion method, a press method, or a casting method. As a specific example, when the press method is employed, the copolymer can be formed into a film by preparing a pellet of the copolymer and pressing it with a hot press. Moreover, the conditions of the hot press are not particularly limited, but generally, the temperature is 120 to 200 ° C. and the pressure is 1 to 10 MPa. When the casting method is employed, for example, the copolymer is dissolved in a solvent to prepare a polymer solution, which is cast on a flat surface to volatilize the solvent and form a film. The solvent is not particularly limited, and examples thereof include 1,4-dioxane, dimethyl carbonate, chloroform, acetone and the like. The film thus produced can be used as an adhesion prevention film as it is.

  The anti-adhesion film of the present invention can exhibit an anti-adhesion function without causing cracks for a sufficient period even when wound on a tendon or the like as described above or when used in a curved state in a living body. it can. For this reason, the adhesion-preventing film of the present invention is particularly useful for winding and for use in a curved state.

  The method of use in a living body is not particularly limited, and can be arranged in an obstetrics and gynecology region, an abdominal region, or the like, but is suitable for use in, for example, a curved affected part. Specifically, for example, in addition to the use of bones and joints such as legs and arms, in particular, to affected parts having a diameter of about 1 to 20 mm, tendons, bones, joints, blood vessels, lymphatic vessels, fallopian tubes, etc. Suitable for use. When a conventional anti-adhesion film is wound on such an affected area, physical force is applied to the film as compared with the case where the film is simply placed on the abdomen as described above. Cracks occur inside. However, according to the adhesion-preventing film of the present invention, even if it is used in a curved state in such an affected area or used by being wound, cracks do not occur during the treatment period, and the affected area and the surrounding tissue are sufficiently produced. Can be physically separated from each other. Specifically, when wound on an affected part such as a tendon, for example, the crack is prevented from occurring for about 3 to 6 weeks, and then decomposed and absorbed into the living body. The period necessary for preventing adhesion of tendons and the like generally requires about 3 to 4 weeks. Therefore, it can be said that the adhesion preventing film of the present invention has a sufficient adhesion preventing effect.

  EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention further more concretely, this invention is not limited to these.

  Lactide-caprolactone copolymer was synthesized by reacting 100 parts by mass of L-lactide and 52.8 parts by mass of ε-caprolactone in the presence of tin octylate (50 ppm) at a reaction temperature of 170 ° C. under reduced pressure for 16 hours. The synthesized copolymer had a weight average molecular weight (Mw) of 800,000 and a molar ratio (A: B) of lactide (A) to caprolactone (B) of 75:25. The obtained lactide-caprolactone copolymer pellets were pressed by a hot press machine at 140 ° C. and 10 MPa to obtain a copolymer film having a thickness of 150 μm.

(Measurement of weight average molecular weight)
The lactide-caprolactone copolymer was dissolved in chloroform, and the weight average molecular weight was measured in terms of standard polystyrene using GPC (gel permeation chromatography, developing solvent: chloroform).

(Measurement of molar ratio of copolymer)
Using a dried lactide-caprolactone copolymer, ¹ H NMR spectrum was measured. The vicinity of 5.2 ppm was lactide and the vicinity of 4.1 ppm was a caprolactone peak, and the molar ratio of lactide to caprolactone was determined from the ratio of the integrated values of these peaks.

  The skin of the forelimb finger of a dog (beagle dog, weight 8 kg) was incised, and the tendon sheath was further incised to expose the flexor tendon in the tendon sheath. The copolymer film (length 10 mm, width 20 mm) was sterilized with ethylene oxide gas (EOG), and then sown onto the flexor tendon, and the copolymer film was sutured and fixed to the tendon. Then, the incision was sutured to fix the cast. Three weeks after the implantation of the copolymer film, the dog was sacrificed, the surgical site was incised along the tendon, and the implanted copolymer film was removed to confirm its state. A similar test was conducted on a total of 19 copolymer films.

  When the copolymer film was visually observed, no cracks were observed in all the films. A photograph of the extracted copolymer film is shown in FIG. Furthermore, when the surface of the copolymer film was observed using a scanning electron microscope (SEM), no erosion of the film surface was observed even by SEM observation.

  The same operation as in Example 1 was carried out except that a copolymer obtained by reacting 100 parts by mass of L-lactide and 79 parts by mass of ε-caprolactone was used (one sample). The obtained lactide-caprolactone copolymer had a weight average molecular weight of 500,000, and the molar ratio of lactide (A) to caprolactone (B) (A: B) was 65:35. As a result, as in Example 1, no cracks were confirmed in the film by visual observation.

  The same operation as in Example 1 was carried out except that a copolymer obtained by reacting 100 parts by mass of L-lactide and 42.6 parts by mass of ε-caprolactone was used (one sample). The obtained lactide-caprolactone copolymer had a weight average molecular weight of 450,000, and the molar ratio (A: B) of lactide (A) to caprolactone (B) was 80:20. As a result, as in Example 1, no cracks were confirmed in the film by visual observation.

(Comparative Example 1)
The same operation as in Example 1 was carried out except that a copolymer obtained by reacting 100 parts by mass of L-lactide and 119 parts by mass of ε-caprolactone was used (6 samples). The weight-average molecular weight of the obtained lactide-caprolactone copolymer was 600,000, and the molar ratio (A: B) between lactide (A) and caprolactone (B) was 50:50.

  When each specimen was visually observed, a large number of cracks of about 1 to 20 mm were confirmed in all the films, and cracks were generated mainly along the longitudinal direction of the tendon. A photograph of the extracted copolymer film is shown in FIG. Note that cracks similar to those in FIG. 2 were confirmed for any of the copolymer films. Furthermore, when the surface of the film was observed by SEM, erosion (roughness of the surface) was confirmed all over the film surface even in a portion where no crack was generated. Since the copolymer film of Comparative Example 1 has a high caprolactone ratio, the flexibility is higher than that of the copolymer films of the Examples. However, since the copolymer film of the comparative example has cracks caused by winding, it can be seen from this result that the occurrence of cracks due to winding cannot be prevented simply by improving the flexibility.

(Comparative Example 2)
The same operation as in Example 1 was carried out except that a copolymer obtained by reacting 100 parts by mass of L-lactide and 85.3 parts by mass of ε-caprolactone was used (one sample). The weight-average molecular weight of the obtained lactide-caprolactone copolymer was 400,000, and the molar ratio (A: B) of lactide (A) to caprolactone (B) was 60:40. As a result of visual observation of each specimen, as in Comparative Example 1, a large number of cracks of about 1 to 20 mm were confirmed in one specimen film, and cracks occurred mainly along the long axis direction of the tendon. .

(Comparative Example 3)
The same operation as in Example 1 was performed except that a copolymer obtained by reacting 100 parts by mass of L-lactide and 19.8 parts by mass of ε-caprolactone was used. The obtained lactide-caprolactone copolymer had a weight average molecular weight of 350,000, and the molar ratio (A: B) of lactide (A) to caprolactone (B) was 90:10. However, the produced film was so hard that it could not be attached to the tendon.

  The same EOG sterilized copolymer film (length 10 mm, width 20 mm) as in Example 1 was rubbed against a sterilized Teflon (registered trademark) rod (diameter 1.5 mm, length 20 mm). A specimen was sutured with a suture and adhered and fixed to the Teflon (registered trademark) rod. The back skin of a dog (beagle dog, body weight 8 kg) was incised and the specimen was implanted subcutaneously, and then the incision was sutured. At the time of implantation, the specimen was only inserted into a subcutaneous pocket made by making a cut in the back of the dog, and was not fixed to the subcutaneous tissue or the like. Three weeks after the implantation of the specimen, the dog was sacrificed, the surgical site was cut open, the specimen was removed, and the state was confirmed (3 specimens).

  When each of the extracted specimens was visually observed, no cracks were confirmed in all the films. Furthermore, when the surface of the copolymer film was observed using a scanning electron microscope (SEM), no erosion of the film surface was observed even by SEM observation.

(Comparative Example 4)
The same operation as in Example 4 was carried out except that the copolymer film prepared in Comparative Example 1 was used (6 samples). Visual inspection of each specimen removed revealed that many cracks of about 1 to 20 mm were observed in all films, and cracks occurred mainly along the long axis direction of the Teflon rods that were pinched. It was.

  Table 1 below shows the observation results of the presence or absence of visual cracks in each example and comparative example.

  As shown in Table 1, when the adhesion preventing film of the example was used, the occurrence of cracks was not confirmed at all. In contrast, the adhesion preventing film of the comparative example cracked with a high probability, and the adhesion preventing film of the comparative example 3 could not be wound. Further, from the results of Example 4, it was found that the effect of preventing cracks was also effective at sites other than tendons.

  From the above, by setting the molar ratio of lactide and caprolactone within a predetermined range, a copolymer film having appropriate flexibility and capable of preventing the occurrence of cracks during use can be obtained. all right.

  Thus, according to the adhesion-preventing film of the present invention, it has moderate flexibility and can prevent cracks during use. For this reason, for example, even when the film is used in a curved state or a wound state, and the physical force is applied to the film, it can exhibit an adhesion preventing function for a sufficient period of time, especially for treatment. It can be said that it is useful for use on tendons that require time and require winding of the anti-adhesion film.

FIG. 1 is a photograph showing an adhesion preventing film in an example of the present invention. FIG. 2 is a photograph showing an adhesion preventing film in a comparative example of the present invention.

Claims (8)

An anti-adhesion film comprising a copolymer of lactide and caprolactone,
The anti-adhesion film is a non-porous film;
The adhesion preventing film, wherein a molar ratio of lactide to caprolactone in the copolymer is in a range of 65:35 to 80:20. The adhesion prevention film according to claim 1, wherein the adhesion prevention film is a film for use in a curved state in a living body. The adhesion prevention film according to claim 1, wherein the adhesion prevention film is a winding film. The adhesion prevention film is a film for winding to at least one site selected from the group consisting of nerves, tendons, bones, joints, blood vessels, lymphatic vessels, and fallopian tubes. The adhesion preventing film according to one item. The adhesion prevention film according to any one of claims 1 to 4, wherein the adhesion prevention film has a thickness in a range of 50 to 300 µm. The adhesion preventing film according to any one of claims 1 to 5, wherein a molar ratio of lactide to caprolactone in the copolymer is 75:25. The adhesion preventing film according to any one of claims 1 to 6, wherein the copolymer has a weight average molecular weight in the range of 100,000 to 1,500,000. The adhesion preventing film according to any one of claims 1 to 7, wherein an average chain length of lactide in the copolymer is 10 or less.

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