JP7456733B2 - Bone synthesis materials - Google Patents
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- JP7456733B2 JP7456733B2 JP2019111221A JP2019111221A JP7456733B2 JP 7456733 B2 JP7456733 B2 JP 7456733B2 JP 2019111221 A JP2019111221 A JP 2019111221A JP 2019111221 A JP2019111221 A JP 2019111221A JP 7456733 B2 JP7456733 B2 JP 7456733B2
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Description
本発明は、骨が再生するまでの間充分な強度で骨を固定できるとともに骨の再生後は速やかに体内に吸収される骨接合材料に関する。 The present invention relates to an osteosynthesis material that is capable of fixing bones with sufficient strength until bone regeneration, and that is quickly absorbed into the body after bone regeneration.
従来から、骨折が治癒するまで骨を固定する骨接合材料としてステンレス、セラミック等より成るワイヤー、プレート、ねじ、ピン、ビス、ステープル、クリップ、ロッド等が用いられている。しかし、金属やセラミックからなる骨接合材料は、人体に吸収されないことから治癒後も体内に残存し、また、これらの骨接合材料は、ＳＵＳ－３１６のステンレス製のもので３２３Ｎ／ｍｍ２程度、セラミック製のもので２４５～４９０Ｎ／ｍｍ２程度と、実用上充分な曲げ強度を有する一方で、人骨に比べて剛性が高すぎることから、適用部の骨が削られたり、持続刺激によって局部の骨の融解、新生骨の強度低下、再生骨の成長遅延等を生じたりする恐れがあるという問題点があった。 Conventionally, wires, plates, screws, pins, screws, staples, clips, rods, etc. made of stainless steel, ceramics, etc. have been used as osteosynthesis materials to fix bones until a fracture has healed. However, bone-synthesizing materials made of metal or ceramics are not absorbed by the human body, so they remain in the body even after healing . Ceramic ones have a bending strength of about 245 to 490 N/ mm2 , which is sufficient for practical use, but because the rigidity is too high compared to human bone, the bone at the application site may be scraped or the local area may be damaged by continuous stimulation. There are problems in that there is a risk of bone melting, a decrease in the strength of new bone, and a delay in the growth of regenerated bone.
これに対して、ポリ－Ｌ－乳酸等の生体吸収性材料からなる骨接合材料が開発されている。例えば、特許文献１には、生体吸収性材料の成形物を、該ポリマーのガラス転移点以上であって融点以下の温度で静水圧押出しして、生体吸収性材料の分子が長軸方向に配向した高密度成形体であって、浮沈法で測定した密度が１．２６０ｇ／ｃｍ３以上である骨接合材料が開示されている。 In response, osteosynthesis materials made of bioabsorbable materials such as poly-L-lactic acid have been developed. For example, in Patent Document 1, a molded product of a bioabsorbable material is hydrostatically extruded at a temperature above the glass transition point and below the melting point of the polymer, so that the molecules of the bioabsorbable material are oriented in the longitudinal direction. Disclosed is an osteosynthesis material which is a high-density molded article and has a density of 1.260 g/cm 3 or more as measured by a float-sink method.
しかしながら、従来のポリ－Ｌ－乳酸からなる骨接合材料は、体内での分解速度が遅く、成長が早い小児の治療には適さない場合もあった。 However, conventional osteosynthesis materials made of poly-L-lactic acid have a slow decomposition rate in the body and are sometimes unsuitable for treatment of rapidly growing children.
本発明は、上記現状に鑑み、骨が再生するまでの間充分な強度で骨を固定できるとともに骨の再生後は速やかに体内に吸収される骨接合材料を提供することを目的とする。 In view of the above-mentioned current situation, an object of the present invention is to provide an osteosynthesis material that can fix bones with sufficient strength until the bones regenerate, and that is quickly absorbed into the body after the bones regenerate.
本発明は、生体吸収性材料からなり、重量平均分子量が１４万以上３２万以下である骨接合材料である。
以下に本発明を詳述する。
The present invention is an osteosynthesis material made of a bioabsorbable material and having a weight average molecular weight of 140,000 to 320,000.
The present invention will be explained in detail below.
本発明者らは、鋭意検討の結果、驚くべきことに生体吸収性材料からなる骨接合材料において、重量平均分子量を特定の範囲とすることで、骨が再生するまでの間充分な強度を有する骨接合材料が得られることを見出し、本発明を完成するに至った。 As a result of intensive studies, the present inventors have surprisingly found that by setting the weight average molecular weight within a specific range, bone-synthesis materials made of bioabsorbable materials have sufficient strength until bone regeneration. The present inventors have discovered that a bone-synthesizing material can be obtained, and have completed the present invention.
本発明の骨接合材料は、生体吸収性材料からなる。
骨接合材料を生体吸収性材料によって構成することで、骨接合材料が時間の経過とともに体内へ徐々に吸収されることから、後に手術によって取り出す必要がない。
The osteosynthesis material of the present invention is made of bioabsorbable material.
By constructing the bone-synthesis material from a bioabsorbable material, the bone-synthesis material is gradually absorbed into the body over time, so there is no need to remove it later through surgery.
上記生体吸収性材料としては、例えば、ポリグリコリド、ポリラクチド、ポリ－ε－カプロラクトン、ラクチド－グリコール酸共重合体、グリコリド－ε－カプロラクトン共重合体、ラクチド－ε－カプロラクトン共重合体、ポリクエン酸、ポリリンゴ酸、ポリ－α－シアノアクリレート、ポリ－β－ヒドロキシ酸、ポリトリメチレンオキサレート、ポリテトラメチレンオキサレート、ポリオルソエステル、ポリオルソカーボネート、ポリエチレンカーボネート、ポリ－γ－ベンジル－Ｌ－グルタメート、ポリ－γ－メチル－Ｌ－グルタメート、ポリ－Ｌ－アラニン、ポリグリコールセバスチン酸等の合成高分子や、デンプン、アルギン酸、ヒアルロン酸、キチン、ペクチン酸及びその誘導体等の多糖類や、ゼラチン、コラーゲン、アルブミン、フィブリン等のタンパク質等の天然高分子等が挙げられる。なかでも、体内での分解速度が骨接合材料として用いるのに適していることからラクチド－グリコール酸共重合体であることが好ましい。なお、本明細書においてラクチドは、Ｌ－ラクチド、Ｄ－ラクチド、Ｄ，Ｌ－ラクチド（ラセミ体）のいずれをも含むが、好ましくはＬ－ラクチドである。これらの生体吸収性材料は単独で用いてもよく、２種以上を併用してもよい。 Examples of the bioabsorbable materials include polyglycolide, polylactide, poly-ε-caprolactone, lactide-glycolic acid copolymer, glycolide-ε-caprolactone copolymer, lactide-ε-caprolactone copolymer, polycitric acid, Polymalic acid, poly-α-cyanoacrylate, poly-β-hydroxy acid, polytrimethylene oxalate, polytetramethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, poly-γ-benzyl-L-glutamate, Synthetic polymers such as poly-γ-methyl-L-glutamate, poly-L-alanine, polyglycol sebastic acid, polysaccharides such as starch, alginic acid, hyaluronic acid, chitin, pectic acid and their derivatives, gelatin, Examples include natural polymers such as proteins such as collagen, albumin, and fibrin. Among these, lactide-glycolic acid copolymer is preferred because its decomposition rate in the body is suitable for use as a bone-synthesis material. In this specification, lactide includes any of L-lactide, D-lactide, and D,L-lactide (racemic form), but L-lactide is preferred. These bioabsorbable materials may be used alone or in combination of two or more.
上記生体吸収性材料がラクチド―グリコール酸共重合体である場合、ラクチドとグリコール酸のモル比が７０：３０～９５：５であることが好ましい。このような比率でラクチドとグリコール酸を含むラクチド―グリコール酸共重合体を用いることで、骨の再生まで充分な強度を有する骨接合材料とすることができる。上記ラクチド―グリコール酸共重合体におけるラクチドとグリコール酸のモル比は、７５：２５～９０：１０であることがより好ましく、７９：２１～８５：１５であることが更に好ましい。 When the bioabsorbable material is a lactide-glycolic acid copolymer, the molar ratio of lactide and glycolic acid is preferably 70:30 to 95:5. By using a lactide-glycolic acid copolymer containing lactide and glycolic acid in such a ratio, an osteosynthesis material having sufficient strength up to bone regeneration can be obtained. The molar ratio of lactide and glycolic acid in the lactide-glycolic acid copolymer is more preferably from 75:25 to 90:10, and even more preferably from 79:21 to 85:15.
本発明の骨接合材料は、重量平均分子量が１４万以上３２万以下である。
従来の生分解性材料を用いた骨接合材料は、体内での吸収速度が速く、骨の再生が完了するまで充分な強度維持することが難しかった。本発明の骨接合材料は、驚くべきことに骨接合材料の重量平均分子量を上記範囲とすることで、骨が再生するまでの間充分な強度で骨を固定することができる。また、骨の再生後は早期に体内へ吸収されるため、体内での異物反応を抑えることもできる。骨の再生が完了するまでの強度をより向上させるとともに、骨の再生後には骨接合材料を早く生体内へ吸収させる観点から、上記骨接合材料の重量平均分子量は１８万以上が好ましく、２０万以上がより好ましく、３０万以下であることが好ましく、２８万以下であることが更に好ましい。上記重量平均分子量を上記範囲に調節する方法としては、原料である生体吸収性材料の重量平均分子量を調節する方法が挙げられるが、骨接合材料の重量平均分子量は原料の重量平均分子量のみによって決定されるものではなく、骨接合材料の製造工程の条件や処理等によっても影響される。
なお、ここで重量平均分子量とは、ＧＰＣ（Ｇｅｌ Ｐｅｒｍｅａｔｉｏｎ Ｃｈｒｏｍａｔｏｇｒａｐｈｙ：ゲルパーミエーションクロマトグラフィ）による標準ポリスチレン換算の重量平均分子量である。具体的には、カラム温度４０℃において溶出液としてクロロホルム、カラムとして細孔多分散型有機溶媒系カラム（例えば、ＳＨＯＤＥＸ ＧＰＣカラム ＬＦ－８０、昭和電工社製）、ＧＰＣ装置として日立ハイテクノロジーズ社製ＬａＣｈｒｏｍ Ｅｌｉｔｅシステムを用いて、ポリスチレン標準により決定することができる。
The bone-synthesis material of the present invention has a weight average molecular weight of 140,000 to 320,000.
Conventional osteosynthesis materials using biodegradable materials have a high rate of absorption in the body, making it difficult to maintain sufficient strength until bone regeneration is complete. Surprisingly, the bone-synthesizing material of the present invention can fix bones with sufficient strength until the bone regenerates by setting the weight-average molecular weight of the bone-synthesizing material within the above range. Additionally, since it is quickly absorbed into the body after bone regeneration, it can also suppress foreign body reactions within the body. In order to further improve the strength until bone regeneration is completed and to allow the osteosynthesis material to be quickly absorbed into the body after bone regeneration, the weight average molecular weight of the osteosynthesis material is preferably 180,000 or more, and preferably 200,000 or more. The above is more preferable, it is preferably 300,000 or less, and even more preferably 280,000 or less. A method for adjusting the weight average molecular weight within the above range includes a method of adjusting the weight average molecular weight of the bioabsorbable material that is the raw material, but the weight average molecular weight of the bone-synthesis material is determined only by the weight average molecular weight of the raw material. However, it is also influenced by the conditions and processing of the manufacturing process of the osteosynthesis material.
Note that the weight average molecular weight herein is a weight average molecular weight in terms of standard polystyrene determined by GPC (Gel Permeation Chromatography). Specifically, the eluent was chloroform at a column temperature of 40°C, the column was a polydisperse pore organic solvent column (for example, SHODEX GPC column LF-80, manufactured by Showa Denko), and the GPC device was manufactured by Hitachi High Technologies. It can be determined with polystyrene standards using the LaChrom Elite system.
本発明の骨接合材料の形状は特に限定されないが、プレート状やダンベル状等が挙げられる。また、骨接合材料を骨に固定するために、骨接合材料と同じ材料をねじ状としたものも本発明に含まれる。更に、本発明の骨接合材料のねじを通す穴の大きさや配置は適用する骨の部位に応じて適宜調節することができる。 The shape of the osteosynthesis material of the present invention is not particularly limited, but examples include plate shape and dumbbell shape. Further, the present invention also includes screw-shaped screws made of the same material as the osteosynthesis material in order to fix the osteosynthesis material to the bone. Furthermore, the size and arrangement of the holes through which the screws of the osteosynthesis material of the present invention are passed can be adjusted as appropriate depending on the bone site to which the material is applied.
本発明の骨接合材料は、厚みが０．５ｍｍ以上２．０ｍｍ以下であることが好ましい。骨接合材料の厚みが上記範囲であることで、骨が再生するまでの間充分な強度を維持できるとともに、骨の再生後はより早く体内へ吸収されるようにすることができる。上記厚みは、０．９ｍｍ以上であることがより好ましく、１．５ｍｍ以下であることがより好ましい。 The osteosynthesis material of the present invention preferably has a thickness of 0.5 mm or more and 2.0 mm or less. When the thickness of the osteosynthesis material is within the above range, sufficient strength can be maintained until the bone regenerates, and after the bone regenerates, it can be absorbed into the body more quickly. The thickness is more preferably 0.9 mm or more, and more preferably 1.5 mm or less.
本発明の骨接合材料の製造方法は特に限定されず、例えば、射出成形や切削をすることで製造することができる。 The method of manufacturing the bone-synthesizing material of the present invention is not particularly limited, and can be manufactured by, for example, injection molding or cutting.
本発明によれば、骨が再生するまでの間充分な強度で骨を固定できるとともに骨の再生後は速やかに体内に吸収される骨接合材料を提供することができる。 According to the present invention, it is possible to provide an osteosynthesis material that can fix a bone with sufficient strength until the bone regenerates and is quickly absorbed into the body after the bone regenerates.
以下に実施例を掲げて本発明を更に詳しく説明するが、本発明はこれら実施例のみに限定されるものではない。 The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.
（実施例１）
骨接合材料の原料としてラクチド（Ｌ体）－グリコール酸共重合体（ラクチドに由来する構成単位：ε－カプロラクトンに由来する構成単位のモル比＝８２：１８、重量平均分子量：２８万）を準備した。
上記原料を射出成形し、切削加工によりネジ挿入孔を形成することにより、４ｍｍ間隔に直径１．９ｍｍの穴を有する、幅５．７５ｍｍ、長さ２６ｍｍ、厚み０．９５ｍｍの板状の骨接合材料を得た。得られた骨接合材料について、日立ハイテクノロジーズ社製ＬａＣｈｒｏｍ Ｅｌｉｔｅシステム及び細孔多分散型有機溶媒系カラム（ＳＨＯＤＥＸ ＧＰＣカラム ＬＦ－８０）を用いて、カラム温度４０℃、溶出液クロロホルムの条件でＧＰＣ測定を行ったところ、重量平均分子量は２６万であった。
(Example 1)
Prepare a lactide (L-form)-glycolic acid copolymer (molar ratio of constituent units derived from lactide: constituent units derived from ε-caprolactone = 82:18, weight average molecular weight: 280,000) as a raw material for bone-synthesis material. did.
By injection molding the above raw material and forming screw insertion holes by cutting, a plate-shaped osteosynthesis with a width of 5.75 mm, a length of 26 mm, and a thickness of 0.95 mm has holes of 1.9 mm in diameter at 4 mm intervals. I got the material. The obtained osteosynthesis material was subjected to GPC using the Hitachi High-Technologies LaChrom Elite system and a pore polydisperse organic solvent column (SHODEX GPC column LF-80) at a column temperature of 40°C and an eluent of chloroform. When measured, the weight average molecular weight was 260,000.
（実施例２）
形状を３．７ｍｍ間隔に直径２．３ｍｍの穴を有する、幅６．５ｍｍ、長さ２４．５ｍｍ、厚み１．４ｍｍの板状とした以外は実施例１と同様にして骨接合材料を得た。
(Example 2)
The osteosynthesis material was obtained in the same manner as in Example 1, except that the shape was a plate with a width of 6.5 mm, a length of 24.5 mm, and a thickness of 1.4 mm, with holes of 2.3 mm in diameter at 3.7 mm intervals. Ta.
（実施例３）
形状を３．７ｍｍ間隔に直径２．３ｍｍの穴を有する、幅５．０ｍｍ、長さ２３ｍｍ、厚み１．４ｍｍのダンベル状とした以外は実施例１と同様にして骨接合材料を得た。
Example 3
A bone fixing material was obtained in the same manner as in Example 1, except that the shape was a dumbbell shape having holes of 2.3 mm diameter spaced 3.7 mm apart and measuring 5.0 mm in width, 23 mm in length and 1.4 mm in thickness.
（比較例１）
ラクトソーブ（Ｚｉｍｍｅｒ ｂｉｏｍｅｔ社製、（品番）９１５－２４１３、ラクチド（Ｌ体）－グリコール酸共重合体、幅５．６ｍｍ、長さ２２．９ｍｍ、厚み０．９ｍｍ、穴の直径１．５ｍｍ）をそのまま用いた。実施例１と同様の方法で重量平均分子量を測定したところ１３万であった。
(Comparative example 1)
Lactosorb (manufactured by Zimmer biomet, (product number) 915-2413, lactide (L form)-glycolic acid copolymer, width 5.6 mm, length 22.9 mm, thickness 0.9 mm, hole diameter 1.5 mm) Used as is. The weight average molecular weight was measured in the same manner as in Example 1 and found to be 130,000.
（比較例２）
ラクトソーブ（Ｚｉｍｍｅｒ ｂｉｏｍｅｔ社製、（品番）９１５－２２１０、ラクチド（Ｌ体）－グリコール酸共重合体、幅６．９ｍｍ、長さ２１．２ｍｍ、厚み１．４ｍｍ、穴の直径２．０ｍｍ）をそのまま用いた。実施例１と同様の方法で重量平均分子量を測定したところ１３万であった。
(Comparative example 2)
Lactosorb (manufactured by Zimmer biomet, (product number) 915-2210, lactide (L-form)-glycolic acid copolymer, width 6.9 mm, length 21.2 mm, thickness 1.4 mm, hole diameter 2.0 mm) Used as is. The weight average molecular weight was measured in the same manner as in Example 1 and found to be 130,000.
＜評価＞
実施例、比較例で得られた骨接合材料について以下の方法により評価を行った。
結果を表１に示した。
<Evaluation>
The osteosynthesis materials obtained in Examples and Comparative Examples were evaluated by the following method.
The results are shown in Table 1.
（１）耐曲げ性の評価
オートグラフを用いて３点曲げ試験を行い骨接合材料の曲げ方向に対する破断強力を測定することで、耐曲げ性を評価した。
(1) Evaluation of bending resistance The bending resistance was evaluated by performing a three-point bending test using an autograph and measuring the breaking strength of the bone-synthesis material in the bending direction.
（２）耐引張性の評価
オートグラフを用いてＪＩＳ規格のＫ７１１３（プラスチックの引張試験方法）に準じて接合材料の引張方向に対する破断強力を測定することで、耐引張性を評価した。
(2) Evaluation of tensile resistance Tensile resistance was evaluated by measuring the breaking strength of the bonding material in the tensile direction using an autograph according to JIS standard K7113 (Plastic tensile test method).
（３）分解性の評価
５０℃のＰＢＳに得られた骨接合材料を浸漬し、所定の時間経過したものについて上記耐曲げ性の評価と同様の方法で破断強力を測定した。得られた破断強力を上記耐曲げ性の評価で得られた破断強力で除することにより強力保持率（％）を算出することで、骨接合材料の分解性を評価した。なお、５０℃のＰＢＳに浸漬したものは生体内の約８倍の速度で分解するものと考えられる。
(3) Evaluation of degradability The obtained osteosynthesis material was immersed in PBS at 50° C., and after a predetermined period of time, the breaking strength was measured in the same manner as in the above evaluation of bending resistance. The degradability of the osteosynthesis material was evaluated by calculating the strength retention rate (%) by dividing the obtained breaking strength by the breaking strength obtained in the evaluation of bending resistance. It is thought that those immersed in PBS at 50°C are decomposed at a rate approximately 8 times faster than in vivo.
本発明によれば、骨が再生するまでの間充分な強度で骨を固定できるとともに骨の再生後は速やかに体内に吸収される骨接合材料を提供することができる。
According to the present invention, it is possible to provide an osteosynthesis material that can fix a bone with sufficient strength until the bone regenerates and is quickly absorbed into the body after the bone regenerates.
Claims (1)
前記骨接合材料のＧＰＣによる標準ポリスチレン換算の重量平均分子量が２０万以上２８万以下であり、
前記生体吸収性材料がラクチド－グリコール酸共重合体であり、前記ラクチドと前記グリコール酸とのモル比が７９：２１～８５：１５である
骨接合材料。
An osteosynthesis material made of an injection molded bioabsorbable material,
The weight average molecular weight of the bone-synthesis material calculated by GPC in terms of standard polystyrene is 200,000 or more and 280,000 or less,
The bone-synthesis material wherein the bioabsorbable material is a lactide-glycolic acid copolymer , and the molar ratio of the lactide to the glycolic acid is 79:21 to 85:15 .
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