Bag for bone augmentation and method for producing same

Abstract

A bag (1) is for use in bone augmentation, and includes a first film (2a) and a second film (2b) obtained by using a biodegradable component as a material. The in-vivo decomposition time of the first film (2a) is equal to or greater than the in-vivo decomposition time of the second film (2b).

Description

Bone augmentation bag and method of manufacturing same

[0001] The present invention relates to a pouch used for bone augmentation and a method for producing the same.

[0002] There are many cases where there is a lack of bone when implant treatment is performed (see Figure 1 (A) (D)). In such cases, bone augmentation (bone grafting) is performed using a non-resorbable or resorbable barrier membrane in addition to filling with bone substitute. When a tooth is extracted, the alveolar bone surrounding the tooth is resorbed, so resorbable barrier membranes are used very frequently.

[0003] Existing absorbable barriers (absorbable membranes) are sheets of solidified absorbable components (poly-L-lactic acid / poly-D-lactic acid; see Non-Patent Documents 1-3) and are available from various companies. Since an unstable barrier reduces the amount of bone augmentation, the barrier must be stabilized to prevent movement in order to achieve successful bone augmentation. Some groups recommend using barrier fixation pins to stabilize the barrier.

[0004] The following are currently available bone grafting procedures for guided bone regeneration (GBR) after gingival incision: (I) A procedure in which a bone substitute made from bone augmentation material is placed at the treatment site in the oral cavity and the procedure is completed by suturing the mucosa (hereinafter referred to as "Procedure I", which uses only a bone substitute). (II) A procedure in which a bone substitute made from bone augmentation material is placed at the treatment site in the oral cavity, an absorbable barrier membrane is placed on top of it, and the procedure is completed by suturing the mucosa (hereinafter referred to as "Procedure II", which uses two types of membrane: a bone substitute and a barrier membrane). (III) A procedure in which, after placing a barrier membrane as in Procedure II, the placed bone substitute and barrier membrane are fixed with sutures to prevent movement, and the procedure is completed by suturing the mucosa (hereinafter referred to as "Procedure III", which uses three types of membrane: a bone substitute, a barrier membrane, and suture). (IV) In order to solve the problems in Type II, a blocking membrane is fixed with pins instead of the sutures used in Type III, and the procedure is completed by suturing the mucosa (hereinafter referred to as "Type IV", and uses three items: a bone substitute, a blocking membrane, and pins. See Figure 1(B)). (V) In order to solve the problems in Type II, a titanium frame or a non-absorbable membrane is placed instead of the blocking membrane to prevent the placed bone substitute from moving, and is fixed with pins, and the procedure is completed by suturing the mucosa (hereinafter referred to as "Type V", and uses three items: a bone substitute, a titanium frame (or a non-absorbable membrane), and pins).

[0005] Kobayashi, Masaharu et al., "Clinical Evaluation of Poly-L-lactic Acid / Poly-D-lactic Acid / Polyglycolic Acid Bioabsorbable Bone Fixing Material in Orthognathic Surgery," Journal of the Japanese Society of Jaw Deformities, 2011, Vol. 21, No. 4, pp. 238-243. Kano, Hiroyuki et al., "Postoperative Jaw Stability in Patients with Mandibular Prognathism Using Poly-L-lactic Acid / Poly-D-lactic Acid / Polyglycolic Acid Bioabsorbable Bone Fixing Material for Maxillary and Maxillary Jaw Positioning Surgery," Journal of the Japanese Society of Jaw Deformities, 2013, Vol. 23, No. 1, pp. 8-14. Kinoshita, Takehiko et al., "Application of Implants to Jaw Reconstruction Sites Using Absorbable Biomaterial Poly-L-lactic Acid and Autologous Bone Marrow and Cancellous Bone Grafts," Head and Neck Tumor, 2000, Vol. 26, No. 3, pp. 525-530. Sato, Shuichi, "Current Status of Periodontal Treatment Using Regenerative Therapy," Nihon University School of Dentistry, 2015, No. 89, p. 93-99

[0006] Bone regeneration requires three conditions: cells, growth factors, and a scaffold (Non-Patent Document 4). Here, a bone substitute can be used as a scaffold, but simply placing a bone substitute, as in Method I, will result in the bone substitute moving from the placement site, halving (reducing) the amount of bone augmentation, and therefore no bone regeneration effect can be expected. Therefore, by preventing the bone substitute from moving, even greater bone regeneration effects can be expected. For this reason, an absorbable barrier membrane is used, as in Methods II to IV above, or a non-absorbable material such as a titanium frame or a non-absorbable membrane is used, as in Method V.

[0007] However, with Method II, the placed bone substitute moves along with the barrier membrane, often reducing the amount of bone growth achieved by the placed bone substitute by half. Furthermore, with Methods III to V, the intraoral manipulation required to fix the bone substitute is difficult and cumbersome, resulting in a significant amount of surgical time. In other words, these methods are not user-friendly. Furthermore, the absorbable barrier membranes currently on the market are single-sheet products.

[0008] The invention disclosed herein has been made in consideration of the above points, and aims to provide a novel bag body and a manufacturing method thereof that can realize user-friendly bone augmentation work.

[0009] The bag of the present disclosure is a bag used for bone augmentation, and is characterized in that it includes a first film and a second film made from biodegradable components, and the biodegradation time of the first film is equal to or longer than the biodegradation time of the second film.

[0010] The bag body of the present disclosure may also include an opening between the first film and the second film that are overlapped and bonded together.

[0011] In the bag of the present disclosure, the biodegradable component may include lactic acid (L)-glycolic acid (G) copolymer.

[0012] In addition, in the bag body of the present disclosure, the L / G ratios of the first film and the second film may be within a range of 45 / 55 to 88 / 12, and the proportion of lactic acid in the L / G ratio of the first film may be equal to or greater than the proportion of lactic acid in the L / G ratio of the second film.

[0013] In the bag body of the present disclosure, the L / G ratio of the first film may be set to a value within a range of 55 / 45 to 88 / 12.

[0014] In the bag body of the present disclosure, the L / G ratio of the second film may be set to a value within a range of 45 / 55 to 55 / 45.

[0015] In the bag of the present disclosure, the intrinsic viscosity of the lactic acid-glycolic acid copolymer may be set within a range of 0.6 dL / g to 1.4 dL / g.

[0016] The pouch of the present disclosure can also accommodate a bone substitute.

[0017] The method for manufacturing the bag body of the present disclosure is a method for manufacturing the bag body of the present disclosure, characterized in that the first film and the second film are formed by spreading a material containing the biodegradable component on a flat surface and then drying it.

[0018] According to the present disclosure, a novel bag body and a manufacturing method thereof can be provided that can realize user-friendly bone augmentation procedures.

[0019] 1A is a diagram showing a state in which alveolar bone is missing before implant treatment (A), a conventional resorbable barrier membrane (B), a bag according to an embodiment of the present disclosure (C), an implant and an artificial tooth (D), and an example of a bag and an implant according to an embodiment of the present disclosure (E). FIG. 1B is a diagram showing an example of the shape of a bag according to an embodiment of the present disclosure. FIG. 1C is a top view showing an opening of a bag according to an embodiment of the present disclosure.

[0020] Hereinafter, exemplary embodiments of the present disclosure will be described with reference to the drawings, but the invention according to the present disclosure is not limited thereto.

[0021] [Bag 1] Figure 1(C) shows a bag 1 according to an exemplary embodiment of the present disclosure. This bag 1 includes a first film 2a and a second film 2b made of biodegradable components and used for bone augmentation (bone grafting), and the biodegradation time of the first film 2a is equal to or longer than the biodegradation time of the second film 2b. That is, the degradation time of the outer first film 2a is the same as or slower (longer) than that of the second film 2b, preferably 4 to 9 months, and more preferably 4 to 6 months. On the other hand, the degradation time of the inner second film 2b is the same as or faster (shorter) than that of the first film 2a, preferably 3 to 6 months, and more preferably 1 to 1.5 months.

[0022] The bag 1 is expected to be absorbed submucosally within approximately three to nine months. Furthermore, in bone augmentation procedures using the bag 1, the bone substitute can be retained within the bag 1. This prevents the bone substitute from moving, which, unlike the above-described methods I and II, reduces the amount of bone growth achieved by the bone substitute. Furthermore, in procedures using the bag 1, the procedure simply involves placing the bag 1 containing the bone substitute at the treatment site (the missing part of the alveolar bone) after gingival incision and suturing the mucosa. Unlike methods III to V, there is no need for an intraoral procedure to fix the bone substitute to the alveolar bone, and there is little risk of damaging the alveolar bone, making this procedure user-friendly (for the surgeon and patient). Furthermore, the procedure is completed more quickly and at a lower cost than methods III to V.

[0023] (First Film 2a, Second Film 2b) The first film 2a and the second film 2b constitute the main body of the bag 1 and are components that house and hold the bone substitute. Examples of biodegradable components that can be used to make the first film 2a and the second film 2b include bovine collagen, atelocollagen, tendon collagen, porcine collagen, and placenta membrane, which have traditionally been used as absorbable membranes. The biodegradable components that make up the first film 2a and the second film 2b preferably contain lactic acid (L)-glycolic acid (G) copolymer (hereinafter also referred to as PLGA). PLGA is characterized by its biodegradability. When implanted in the body, it is hydrolyzed to lactic acid and glycolic acid, which are then metabolized in the body and harmlessly eliminated as water and carbon dioxide. PLGA decomposes more quickly than polylactic acid (PLA) and other materials. When the first film 2a and the second film 2b have different bioabsorption performances, it is preferable to place the first film 2a, which has a longer biodegradation time, closer to the mucosal surface (mucosal side), and the second film 2b, which has a shorter biodegradation time, closer to the alveolar bone (bone side) (see Fig. 1(C)). Because bone regeneration begins from the bone side, the need to fixate the bone substitute contained in the bag 1 is greater on the mucosal side than on the bone side, and it is desirable to maintain the mucosal side portion of the bag 1 (first film 2a) for a long time.

[0024] As demonstrated in the examples (experimental examples), the degradation rate of PLGA in vivo can vary significantly depending on the L / G ratio (the ratio of lactic acid (L) to glycolic acid (G); L:G). While PLGA with an L / G ratio of 50 / 50 is considered to have the highest degradation rate, generally, the higher the glycolic acid (G) content in PLGA (i.e., the lower the L content), the faster it degrades. This is thought to be because polyglycolic acid (PGA) is more sensitive to water than polylactic acid (PLA), resulting in faster degradation. Therefore, assuming that the L / G ratios of the first film 2a and the second film 2b are within the range of 45 / 55 to 88 / 12, it is preferable that the percentage of lactic acid in the L / G ratio of the first film 2a placed on the mucosa side (the value of L in the L:G ratio, where L+G in PLGA is 100) be equal to or greater than the percentage of lactic acid in the L / G ratio of the second film 2b placed on the bone side.

[0025] When a difference in bioabsorption performance is to be achieved between the first film 2a and the second film 2b, the L / G ratio of the first film 2a is preferably 55 / 45 to 88 / 12. Specifically, the L / G ratio of the first film 2a may be within the ranges of 55 / 45 to 72 / 28, 55 / 45 to 75 / 25, 55 / 45 to 82 / 18, 55 / 45 to 85 / 15, 72 / 28 to 88 / 12, 78 / 22 to 88 / 12, 75 / 25 to 88 / 12, 82 / 18 to 88 / 12, 85 / 15, or up to 88 / 12. On the other hand, when a difference in bioabsorption performance is to be achieved between the first film 2a and the second film 2b, the L / G ratio of the second film 2b is preferably within the range of 45 / 55 to 55 / 45. Specifically, the L / G ratio of the second film 2b can be set to a value within the range of 45 / 55 to 50 / 50 or 50 / 50 to 55 / 45.

[0026] Furthermore, when there is no difference in bioabsorption performance between the first film 2a and the second film 2b, the L / G ratios of the first film 2a and the second film 2b can be set within a range of 45 / 55 to 88 / 12. Thus, the L / G ratio of the first film 2a may be set within a range of 45 / 55 to 55 / 45 or 50 / 50 to 88 / 12, and the L / G ratio of the second film 2b may be set within a range of 55 / 45 to 88 / 12. As described above, the L / G ratios of the first film 2a and the second film 2b may be set to 45 / 55, 50 / 50, 55 / 45, 72 / 28, 78 / 22, 75 / 25, 82 / 18, 85 / 15, or 88 / 12, and the design can be modified as appropriate depending on the intended use of the bag 1.

[0027] The L / G ratio of PLGA has a significant effect on the degradability (degradation time in the body, bioabsorption performance), mechanical properties, and biocompatibility of the bag 1, and is also considered to be an important factor in widening the range of its applications. １ It can be measured by H-NMR spectroscopy.

[0028] Furthermore, the intrinsic viscosity (IV) value of PLGA is preferably 0.6 dL / g or more and 1.4 dL / g or less, taking into consideration the necessary strength of the bag body 1 and an appropriate hardness in the oral cavity. The IV value can be measured, for example, using an Ubbelohde viscometer in accordance with the United States Pharmacopoeia (USP <911>).

[0029] The bag 1 is preferably foldable and easily shaped. Furthermore, the size (volume) and shape of the bag 1 and the dimensions (thickness, length, etc.) of the first film 2a and the second film 2b are not particularly limited, and may be formed into a rectangular shape ( FIG. 2 ), a disk, a trapezoid, a triangle, etc. Because the bag 1 is placed in the missing portion of the alveolar bone, it can be appropriately designed to match the condition of the teeth or dentition. The bag 1 may be trimmed to fit the actual teeth or dentition when the bone substitute is placed or during treatment. To allow for this, for example, if the bag 1 is rectangular, the length of one side of the bag 1 can be set to 13 mm to 17 mm.

[0030] The breaking strength of the first film 2a and the second film 2b can be 4 N to 14 N, and a reference value for strength for molding is preferably 6 N or more in view of peelability, etc. This breaking strength is the maximum pressure at which a film (15 mm × 60 mm × 0.05 mm) set in a tensile tester (Force Tester MCT-1150 manufactured by A&D) is pulled at a rate of 300 mm / min and breaks or stretches to its full extent.

[0031] (Opening 3) The bag 1 may have an opening 3 between the first film 2a and the second film 2b, which are overlapped and bonded together. For example, if the bag 1 is sheet-shaped, it may be open in one of four directions ( FIG. 2 ), or in two directions. A bone substitute can be inserted into the bag 1 through the opening 3. The width of the opening 3 may be the same as the length of one side of the bag 1 (the first film 2a and the second film 2b), as shown in FIG. 3(A), or may be smaller, as shown in FIG. 3(B). Furthermore, the side of the bag 1 where the opening 3 is provided may be tapered toward the outside of the bag 1, as shown in FIG. 3(C). With such a tapered bag 1, compared to the configuration shown in FIG. 3(A), the bag 1 can be brought into the oral cavity through the gaps between the teeth before and after the tooth loss site without prior trimming, and can be easily slid between the alveolar bone and gums at that site. In other words, this improves operability during treatment. The width of the opening 3 can be appropriately set and changed as long as it allows the bone substitute to be inserted. After the bone substitute is placed inside, the opening 3 may be sealed (including by heat sealing or folding). Note that it is preferable to heat seal the opening 3 during the procedure to prevent leakage of the bone substitute.

[0032] The bone substitute contained in the bag 1 and used for bone augmentation is not particularly limited, and may be autologous bone, allogeneic bone, artificial bone, etc. Bone substitutes from various companies are also available and commercially available materials.

[0033] [Method for Manufacturing Bag 1] The method for manufacturing bag 1 is not limited, but a so-called solution casting method can be used. For example, a prepared PLGA solution is evenly spread (casting) on ​​a smooth surface (a substrate such as glass or a silicon wafer). This is then dried to form a first film 2a and a second film 2b. The first film 2a and the second film 2b are then superimposed and sealed (in the example shown in FIG. 2(A) , sealing is performed in three directions other than the opening 3). In this manner, bag 1 can be manufactured. Furthermore, when bag 1 is manufactured using only one type of film (2a or 2b) (when the biodegradation time of bag 1 is the same on both sides), sealing in two directions may be performed. For example, when preparing a 40 mm x 50 mm film to manufacture a 40 mm x 25 mm bag 1, the long sides (50 mm) may be folded in half and only the 25 mm portions of the two opposing sides (the lengthwise direction in Fig. 2(B)) may be sealed, or the 40 mm and 25 mm portions of the two adjacent sides (the lengthwise and widthwise directions in Fig. 2(C)) may be sealed. In this way, by providing a folding step in the manufacturing process for bag 1 in which first film 2a and second film 2b are formed from the same type of film, the number of sealing operations can be reduced.

[0034] The PLGA solution is prepared by dissolving PLGA in a suitable organic solvent. Examples of organic solvents include chloroform and dichloromethane. This solvent is used to process the PLGA into a film. The PLGA concentration in the solution may vary depending on the film thickness and physical properties desired. In the casting method described above, the viscosity of the PLGA solution is preferably 15 mPa·s or less.

[0035] The prepared PLGA solution can be spread using a spin coater or manually using a pipette or spreader. Drying can be carried out at room temperature or in a temperature-controlled environment to accelerate evaporation of the solvent. The time required for complete drying varies depending on the concentration of the solution and the environmental conditions.

[0036] [Use of bag 1] As described above, the bag 1 is used for bone augmentation (bone grafting). As an example, a bone augmentation method using the bag 1 can include the steps of incising the gums in the oral cavity, placing the bag 1 containing the bone substitute on the missing part of the alveolar bone (see FIG. 1(C)), and suturing the gums. The bone substitute contained in the bag 1 is immobile because it is contained in a bag-like shape. In this way, even when the bone substitute is placed, it can be ensured that it does not move from the placement location.

[0037] In addition, another bone augmentation method using a bag 1 may include a step of incising the gums in the oral cavity, a step of placing a bag 1 containing substitute bone on the missing part of the alveolar bone so as to cover the implant when implanting the implant in the missing part of the alveolar bone (as shown in Figure 1(A)) (see Figure 1(E)), and a step of suturing the gums.

[0038] Another use of the bag 1 of the present disclosure is as a material to be filled into the tooth extraction socket (the cavity left after tooth extraction) after tooth extraction. That is, after tooth extraction, the bag 1 placed in the tooth extraction socket inhibits alveolar bone resorption, and therefore filling the socket with the bag 1 is more effective in increasing bone mass when placing an implant in the future than not filling the socket with the bag 1. This inhibitory effect is significant when the bag 1 is made of multiple films, and it is used to contain a bone substitute. Even in this use, the shape of the bag 1 is not particularly limited, and it can be appropriately deformed (folded) to fit the tooth extraction socket. Furthermore, when the bag 1 is filled into the tooth extraction socket after tooth extraction, the amount of bone substitute used (required) in implant treatment for that patient can be reduced.

[0039] In the bag 1 and the method for manufacturing the bag 1 according to the present disclosure having the above-described configuration, the bag 1 is used for bone augmentation and includes a first film 2 a and a second film 2 b made of biodegradable components, and the biodegradation time of the first film 2 a is equal to or longer than the biodegradation time of the second film 2 b. Furthermore, the bag 1 may contain a bone substitute.

[0040] The bag 1 according to the present disclosure and the bag 1 obtained by the manufacturing method according to the present disclosure are bag-shaped and capable of containing and retaining a bone substitute. Therefore, during bone augmentation treatment, the contained bone substitute can be fixed simply by placing the bag 1 on the missing portion of the alveolar bone, thereby realizing a user-friendly bone augmentation treatment that does not require the complicated procedures of Procedures III to V. Furthermore, the bag 1, which is composed of the first film 2a and the second film 2b made of biodegradable components, is a novel fixation method that differs from the single absorbable barrier membrane used in Procedures II to IV and the titanium frame or non-absorbable membrane used in Procedure V. Furthermore, the bag 1 can also use first films 2a and second films 2b with different biodegradation times (bioabsorption performance), allowing for design depending on the treatment site (mucosal side, bone side).

[0041] Furthermore, in the bag body 1 and the manufacturing method of the bag body 1 according to the present disclosure, an opening 3 may be provided between the first film 2a and the second film 2b that are overlapped and bonded together. In this manner, a bone substitute can be inserted into the bag body 1 through the opening 3. Furthermore, the bag body 1 according to the present disclosure is not limited to one in which two films are overlapped together.

[0042] Furthermore, in the bag 1 and the manufacturing method for the bag 1 according to the present disclosure, the biodegradable component may include lactic acid (L)-glycolic acid (G) copolymer. Using PLGA as the first film 2a and the second film 2b is preferable because it decomposes faster than, for example, polylactic acid alone. It is also possible to use bovine collagen, atelocollagen, tendon collagen, porcine collagen, placenta membrane, lactic acid, or glycolic acid as the biodegradable component. As a combination of biodegradable components for the first film 2a and the second film 2b, one film may be formed from these materials, and the other film may be formed from PLGA.

[0043] In the bag 1 and the method for manufacturing the bag 1 according to the present disclosure, the L / G ratios of the first film 2a and the second film 2b may be within a range of 45 / 55 to 88 / 12, and the proportion of lactic acid in the L / G ratio of the first film 2a may be equal to or greater than the proportion of lactic acid in the L / G ratio of the second film 2b. The L / G ratio of the first film 2a may be within a range of 55 / 45 to 88 / 12, and the L / G ratio of the second film 2b may be within a range of 45 / 55 to 55 / 45. In this manner, the biodegradation time (bioabsorption performance) of each film can be adjusted.

[0044] In the bag 1 and the method for manufacturing the bag 1 according to the present disclosure, the intrinsic viscosity of the lactic acid-glycolic acid copolymer may be in the range of 0.6 dL / g to 1.4 dL / g. It is preferable that the intrinsic viscosity of the PLGA is in this range in terms of the required strength and hardness of the bag 1.

[0045] In the bag 1 and the method for manufacturing the bag 1 according to the present disclosure, the first film 2 a and the second film 2 b may be formed by spreading a material containing a biodegradable component on a flat surface and then drying the material. In this manner, the bag 1 can be easily manufactured.

[0046] The bag body 1 and the method for manufacturing the bag body 1 according to the present disclosure are not limited to the above-described aspects and combinations, and various modifications can be made.

[0047] For example, the bag 1 may include other bioabsorbable films in addition to the first film 2 a and the second film 2 b, and the materials of the other bioabsorbable films may be the same as or different from those of the first film 2 a and the second film 2 b. For example, it is also possible to provide multiple types of absorbent films on one surface of the bag 1.

[0048] The shape of the bag 1 is not limited to a sheet, and may be formed into various shapes such as a cylindrical shape, a cone shape, a sphere shape, a rectangular parallelepiped shape, a tooth shape, etc. depending on the tooth alignment and the missing part of the alveolar bone. Each surface of the bag 1 may have a laminated structure.

[0049] The position of the opening 3 is not limited to between the first film 2a and the second film 2b, and the opening 3 may be formed in the first film 2a or the second film 2b by overlapping the first film 2a and the second film 2b and bonding the edges together (closing the bag body 1 in all four directions). The number of openings 3 is also not limited to one. A plurality of openings 3 may be provided between the overlapping and bonded first film 2a and second film 2b or in each of them.

[0050] The present disclosure will be described in more detail below using examples (experimental examples). Specifically, the bags 1 were manufactured using the following materials, and the degradability (i.e., biodegradation time and bioabsorption performance) of each bag 1 (example) was verified. Note that the first film 2a and the second film 2b were made with the same composition, and therefore will be simply referred to as film or membrane in the following description.

[0051] (1) Experimental Reagents PLGA Solution: PLGA: Ashland DLG 8513 E Lot No. 0002633992, Ashland DLG 8509 A Lot No. 0002480336, Ashland DLG 8507 A Lot No. 0002591847, Ashland DLG 7507 A Lot No. 0002510702, Mitsui Chemicals PLGA 5-50 Dichloromethane (solvent): Fujifilm Wako Pure Chemical Industries, Ltd. Lot No. DLR5072 Additive Tween 80: Kanto Chemical Co., Ltd. Lot No. Food Yellow No. 5: Osaka Food Color Co., Ltd., Lot No. R10401M1 (used in Example 5 as a colorant for type identification) Riboflavin: Tokyo Chemical Industry Co., Ltd., Lot No. CJCTO-YT (used in Example 6 as a colorant for type identification) Elution solution: Polyvinyl alcohol EG-05P: Nippon Synthetic Chemical Industry Co., Ltd., Lot No. 68N69 Tween 80: Kanto Chemical Co., Ltd., Lot No. 104K1486 Lactic acid: Kanto Chemical Co., Ltd., Lot No. 010B2087 Distilled water: Kyoei Pharmaceutical Co., Ltd., Lot No. 18D671, Lot No. 18D685 Washing water: Distilled water: Kyoei Pharmaceutical Co., Ltd., Lot No. 18D671, Lot No. 18D685

[0052] (2) Experimental equipment Micrometer: M110-25 manufactured by Mitutoyo Corporation Sealer: POLYSEALER P-200 manufactured by Fuji Impulse Tabletop tension and compression testing machine: Force Tester MCT-1150 manufactured by A&D

[0053] (3) Experimental Method: Bag Preparation: Specified amounts of PLGA and Tween 80 were weighed and dissolved in dichloromethane in a sealed container and left overnight. Each solution volume was 25 mL (32 g). The PLGA solution concentration was 2.5% w / w (0.8 g / 32 g), and the additive content was 0.5% w / w (0.16 g / 32 g, 20% relative to PLGA). The resulting solution was cast into a stainless steel tray. The stainless steel tray dimensions were 105 x 135 mm for a 0.05 mm film thickness and 130 x 195 mm for a 0.03 mm film thickness. After leaving the film to dry overnight, the film was peeled off, visually inspected, and the film thickness was measured. For each example, bag 1 (25 mm x 40 mm) and test pieces (15 mm x 60 mm) were prepared from the peeled film. The test pieces were used to measure breaking strength (tensile speed: 300 mm / min).

[0054] Decomposition Period Confirmation (Dissolution Test): One pouch 1 was precisely weighed into a 125 mL glass container, and 100 mL of dissolution solution (2% PVA aqueous solution: 20% Tween 80 aqueous solution: 0.9% lactic acid aqueous solution / water = 40:1:40 / 200) heated to 37±0.5°C was added. Each container was then capped with a 2 mm-thick septum, fixed, and immersed in a water bath at 37±0.5°C. During the dissolution test, the temperature of the water bath was raised from 37°C to 61°C at a rate of 0.5°C / hour. The container was removed 3 hours (38.5°C), 28 hours (51.0°C), and 48 hours (61.0°C) after the start of the temperature increase, and the solution was filtered. The removed film was washed with water and dried. Weight was measured to confirm the weight retention rate. In Examples 1 to 4, the above method was repeated four times, with each sampling time (3, 28, and 48 hours later) assumed to be 1 to 12 months after placement in the body, and confirmation was performed at nine time points (1, 3, 4, 6, 7, 8, 9, 10, and 12 months). However, in Examples 5 and 6, the above method was repeated twice, with each sampling time assumed to be 1 to 6 months after placement in the body, and confirmation was performed at six time points (1, 2, 3, 4, 5, and 6 months).

[0055] (4) Decomposition Confirmation Test Results [Example 1: DLG 8513 E film (0.05 mm) (L / G ratio: nominal value 85 / 15, specification 82.0 / 18.0 to 88.0 / 12.0, inspection value 84.5 / 15.5 (in accordance with USP <761>) １ H-NMR spectroscopy), IV: 1.30 dL / g, breaking strength: 13.62 N]. The weight retention rate decreased at 3 months and remained almost constant thereafter. The product began to curl up, and by 9 months it had become transparent and brittle when it dried.

[0056] [Example 2: DLG 8509 A film (0.05 mm) (L / G ratio: nominal value 85 / 15, specification 82.0 / 18.0 to 88.0 / 12.0, test value 84.5 / 15.5 (in accordance with USP <761>) １H-NMR spectroscopy), IV: 0.99 dL / g, breaking strength: 12.72 N] The weight retention rate decreased at 3 months and remained almost constant thereafter. The absorbed moisture at 6 and 8 months was difficult to dry and exceeded that of the previous month. At 6 months, changes in appearance began to be observed before and after drying, and the sample became brittle and prone to cracking when dried.

[0057] Example 3: DLG 8507 A film (0.05 mm) (L / G ratio: nominal value 85 / 15, specification 82.0 / 18.0 to 88.0 / 12.0, test value 84.6 / 15.4 (in accordance with USP <761>) １ H-NMR spectroscopy), IV: 0.64 dL / g, breaking strength: 8.36 N]. The weight retention rate dropped significantly at 3 months and then gradually decreased. The appearance became transparent after drying at 4 months, became brittle after drying at 6 months, and was brittle even before drying at 7 months.

[0058] Example 4: DLG 7507 A film (0.05 mm) (L / G ratio: nominal value 75 / 25, specification 72.0 / 28.0 to 78.0 / 22.0, test value 74.9 / 25.1 (in accordance with USP <761>) １ H-NMR spectroscopy), IV: 0.68 dL / g, breaking strength: 8.38 N]. The weight retention rate dropped significantly at 3 months and then gradually decreased. The appearance became transparent after drying at 4 months, became brittle when dried at 4 months, and was brittle even before drying at 7 months.

[0059] [Example 5: PLGA 5-50 colored film (0.05 mm) (L / G ratio: nominal value 50 / 50, specification 45.0 / 55.0 to 55.0 / 45.0, test value 50.5 / 49.5 ( １ H-NMR spectroscopy), IV: 0.50 dL / g, breaking strength: 4.78 N]. The weight retention rate decreased between 2 and 3 months and remained almost constant between 3 and 5 months. It began to decrease again between 5 and 6 months. The film appeared to be curled up until the 2nd month, then became transparent upon drying, but maintained its shape. After drying by the 3rd month, the film became brittle. Furthermore, no difference in physical properties was observed when a dye was added to the film.

[0060] Example 6: DLG 7507 A colored film (0.03 mm) (breaking strength: 7.22 N) The weight retention rate dropped significantly in the second month and then gradually decreased. The film appeared to be curling from the second month onward, becoming transparent upon drying, but retaining its shape. By the sixth month, the film had become quite brittle. Compared to the 0.05 mm film (Example 4), no significant differences were observed in either weight retention rate or appearance. Therefore, it was found that a bag body 1 could be produced without any problems in strength as long as the film thickness was within the range of 0.03 to 0.05 mm.

[0061] (5) Summary: No significant changes (differences) in weight were observed during the maintenance period. Based on appearance and brittleness, the following trends were found in relation to the L / G ratio. If the L / G ratio was 85 / 15, the bag became brittle after six months or more. If the L / G ratio was 75 / 25, the bag became brittle after four months or more. If the L / G ratio was 50 / 50, the bag became brittle after four months or less. These findings suggest that varying the L / G ratio of the first film 2a and the second film 2b constituting the bag 1 results in different biodegradability (in vivo degradation time, bioabsorption performance). Furthermore, if the L / G ratio of the first film 2a is within the range of 55 / 45 to 88 / 12 and the L / G ratio of the second film 2b is within the range of 45 / 55 to 55 / 45, the respective biodegradation times are suggested to be approximately 4 to 9 months and 1 to 4 months, respectively.

Claims

1. A bag used for bone augmentation, comprising a first film and a second film made of biodegradable components, wherein the biodegradation time of the first film is equal to or longer than the biodegradation time of the second film.

2. The bag according to claim 1, wherein an opening is provided between said first film and said second film which are overlapped and bonded together.

3. The bag according to claim 1 or 2, wherein the biodegradable component comprises lactic acid (L)-glycolic acid (G) copolymer.

4. The bag according to claim 3, wherein the L / G ratios of the first film and the second film are within the range of 45 / 55 to 88 / 12, and the proportion of lactic acid in the L / G ratio of the first film is equal to or greater than the proportion of lactic acid in the L / G ratio of the second film.

5. The bag according to claim 3 or 4, wherein the L / G ratio of the first film is within the range of 55 / 45 to 88 / 12.

6. A bag as described in any one of claims 3 to 5, wherein the L / G ratio of the second film is within the range of 45 / 55 to 55 / 45.

7. The bag according to any one of claims 3 to 6, wherein the intrinsic viscosity of the lactic acid-glycolic acid copolymer is in the range of 0.6 dL / g to 1.4 dL / g.

8. A pouch according to any one of claims 1 to 7, containing a bone substitute.

9. A method for manufacturing the bag according to claim 1, wherein the first film and the second film are formed by spreading the material containing the biodegradable component on a flat surface and then drying it.

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