JP2016039879A - Medical material comprising polyamide 4 or copolymer thereof and use thereof - Google Patents
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本発明は、ポリアミド４またはその共重合体を含む医療材料及び使用に関する。 The present invention relates to medical materials and uses comprising polyamide 4 or copolymers thereof.
ポリアミド（ナイロン）は軽さ、強度、耐熱性、弾性及び染色性など点で優れているため、繊維、医療用品、工業材料など多くの用途に使用されている。ポリアミドには所謂ナイロン６やナイロン６６などの多くの種類が存在するが、これらは主に焼却や埋立てなど、多くのエネルギーを要する方法や手間のかかる方法により処分されている。 Polyamide (nylon) is excellent in lightness, strength, heat resistance, elasticity, and dyeability, and is therefore used in many applications such as fibers, medical supplies, and industrial materials. There are many types of polyamides, such as so-called nylon 6 and nylon 66, and these are mainly disposed of by a method requiring a lot of energy such as incineration or landfilling or a time-consuming method.
生体内分解性材料としては各種ポリエステルやポリウレタンが研究されてきた。現在使われているものとしては、ほとんどがポリ乳酸、グリコール酸を主成分としたポリエステルかコポリエステルエーテルであり、手術用の縫合糸や人工骨用途である。近年、iPS細胞に関連した再生医療技術の研究が進められており、生体に適した足場材料が求められている。一方で、ポリアミド４はバイオマスから容易に合成でき、かつ、種々のポリアミド類の中でほぼ唯一、環境中での良好な生分解性を有す材料として注目されている(特許文献１、非特許文献１）。その主鎖はγ-アミノ酪酸で構成されることからポリアミノ酸でもあり、各種タンパク質との親和性が高いことも期待される。 Various polyesters and polyurethanes have been studied as biodegradable materials. Currently used are mostly polyester or copolyester ether based on polylactic acid and glycolic acid, and are used for surgical sutures and artificial bones. In recent years, research on regenerative medical technology related to iPS cells has been advanced, and a scaffold material suitable for a living body is required. On the other hand, polyamide 4 can be easily synthesized from biomass, and is the only material among various polyamides that has attracted attention as a material having good biodegradability in the environment (Patent Document 1, Non-Patent Document 1). Reference 1). Since its main chain is composed of γ-aminobutyric acid, it is also a polyamino acid and is expected to have high affinity with various proteins.
本発明者らはバイオマスから生産されているグルタミン酸を微生物を用いてγ-アミノ酪酸に効率的に変換する方法を報告している(非特許文献２）。ポリアミド４は環境中で生分解される材料であるが、生体内での分解性、細胞毒性、変異原性などの性質は調べられていなかった。 The present inventors have reported a method for efficiently converting glutamic acid produced from biomass into γ-aminobutyric acid using a microorganism (Non-patent Document 2). Polyamide 4 is a material that is biodegraded in the environment, but properties such as in vivo degradability, cytotoxicity, and mutagenicity have not been investigated.
本発明はポリアミド４又はその共重合体の生体内における新たな用途、特に再生医療に有用な医療材料を提供することを目的とする。 An object of the present invention is to provide a medical material useful for new uses in vivo of polyamide 4 or a copolymer thereof, particularly for regenerative medicine.
本発明は、以下の医療材料及び使用を提供するものである。
項１． ポリアミド４のホモポリマーまたはコポリマーを含む、生体内に埋入される医療材料。
項２． ポリアミド４のコポリマーが、2-ピロリドンと環状ジエステルとの開環共重合体、2-ピロリドンと4〜7員環のラクトン類との開環共重合体、及び、2-ピロリドンと脂肪族ポリエステルとのブロック共重合体からなる群から選ばれる少なくとも１種である、項１に記載の医療材料。
項３． 環状ジエステルがラクチド又はグリコリドである、項２に記載の医療材料。
項４． 4〜7員環のラクトン類がβ−プロピオラクトン、β−ブチロラクトン、β−バレロラクトン、３−メチル−β−プロピオラクトン、γ−ブチロラクトン、δ−バレロラクトン、３−メチル−δ−バレロラクトン、４−メチル−δ−バレロラクトン、δ−カプロラクトン、ε−カプロラクトン、３−メチル−ε−カプロラクトン、４−メチル−ε−カプロラクトン、３，３，５−トリメチル−ε−カプロラクトン、３，５，５−トリメチル−ε−カプロラクトン及び７−メチル−ε−カプロラクトンからなる群から選ばれる、項２に記載の医療材料。
項５． さらに他の生体内吸収性ポリマーを含む項１に記載の医療材料。
項６． 他の生体内吸収性ポリマーが、ポリ乳酸、ポリグリコール酸、ポリ-ε-カプロラクトン、グリコール酸と乳酸のコポリマー、乳酸と-ε-カプロラクトンのコポリマー、コラーゲン、カットグット、ゼラチン、アミロース、デキストラン、キチン、キトサン、ポリグルタミン酸、アルギン酸からなる群から選ばれる、項５に記載の医療材料。
項７． 医療材料が、パッチ材、人工心臓弁、ステント、骨接合材、人工心膜、縫合糸、組織補填材、組織補強材、組織被覆材、組織もしくは臓器再生用基材、細胞培養の足場材料、組織補綴材、癒着防止材、クリップ、細胞シート又はDDS基材である、項１に記載の医療材料
項８． ポリアミド４のホモポリマーコポリマーの生体内に埋入される生体内吸収性材料としての使用。
The present invention provides the following medical materials and uses.
Item 1. A medical material implanted in a living body, comprising a homopolymer or copolymer of polyamide 4.
Item 2. A copolymer of polyamide 4 is a ring-opening copolymer of 2-pyrrolidone and a cyclic diester, a ring-opening copolymer of 2-pyrrolidone and a 4- to 7-membered lactone, and 2-pyrrolidone and an aliphatic polyester Item 2. The medical material according to Item 1, which is at least one member selected from the group consisting of block copolymers of:
Item 3. Item 3. The medical material according to Item 2, wherein the cyclic diester is lactide or glycolide.
Item 4. 4- to 7-membered lactones are β-propiolactone, β-butyrolactone, β-valerolactone, 3-methyl-β-propiolactone, γ-butyrolactone, δ-valerolactone, 3-methyl-δ-valero Lactone, 4-methyl-δ-valerolactone, δ-caprolactone, ε-caprolactone, 3-methyl-ε-caprolactone, 4-methyl-ε-caprolactone, 3,3,5-trimethyl-ε-caprolactone, 3,5 Item 3. The medical material according to Item 2, selected from the group consisting of 1,5-trimethyl-ε-caprolactone and 7-methyl-ε-caprolactone.
Item 5. Item 2. The medical material according to Item 1, further comprising another bioabsorbable polymer.
Item 6. Other bioabsorbable polymers include polylactic acid, polyglycolic acid, poly-ε-caprolactone, copolymers of glycolic acid and lactic acid, copolymers of lactic acid and -ε-caprolactone, collagen, cut gut, gelatin, amylose, dextran, chitin Item 6. The medical material according to Item 5, selected from the group consisting of: chitosan, polyglutamic acid, and alginic acid.
Item 7. The medical material is a patch material, artificial heart valve, stent, osteosynthesis material, artificial pericardium, suture thread, tissue filling material, tissue reinforcing material, tissue coating material, tissue or organ regeneration substrate, cell culture scaffolding material, Item 7. A medical material according to Item 1, which is a tissue prosthesis, an adhesion-preventing material, a clip, a cell sheet, or a DDS substrate. Use of a polyamide 4 homopolymer copolymer as a bioabsorbable material embedded in a living body.
本発明により、ポリアミド４のホモポリマーまたはコポリマーがヒトなどの生体内で分解性を有し、かつ、細胞毒性、変異原性を有しないため、再生医療などの医療材料としての用途に好適に使用できることが明らかになった。 According to the present invention, the homopolymer or copolymer of polyamide 4 is degradable in a living body such as a human, and has no cytotoxicity or mutagenicity. Therefore, it is suitable for use as a medical material such as regenerative medicine. It became clear that we could do it.
本発明では、生体内に埋入される医療材料或いは生体内吸収性材料として使用されるポリアミド４またはそのコポリマーは公知であり、公知の方法に従いモノマーとして2-ピロリドンを用いてポリアミド４を製造することができ、或いは2-ピロリドンと環状ジエステルとの開環共重合体、2-ピロリドンと4〜7員環のラクトン類との開環共重合体、及び、2-ピロリドンと脂肪族ポリエステルとのブロック共重合体などを製造することができる。 In the present invention, polyamide 4 or a copolymer thereof used as a medical material or a bioabsorbable material to be implanted in a living body is known, and polyamide 4 is produced using 2-pyrrolidone as a monomer according to a known method. A ring-opening copolymer of 2-pyrrolidone and a cyclic diester, a ring-opening copolymer of 2-pyrrolidone and a 4- to 7-membered lactone, and 2-pyrrolidone and an aliphatic polyester. Block copolymers and the like can be produced.
環状ジエステルとしては、ラクチド、グリコリドが挙げられ、4〜7員環のラクトン類としては、β−プロピオラクトン、β−ブチロラクトン、β−バレロラクトン、３−メチル−β−プロピオラクトン、γ−ブチロラクトン、δ−バレロラクトン、３−メチル−δ−バレロラクトン、４−メチル−δ−バレロラクトン、δ−カプロラクトン、ε−カプロラクトン、３−メチル−ε−カプロラクトン、４−メチル−ε−カプロラクトン、３，３，５−トリメチル−ε−カプロラクトン、３，５，５−トリメチル−ε−カプロラクトン及び７−メチル−ε−カプロラクトンが挙げられる。 Examples of the cyclic diester include lactide and glycolide. Examples of the 4- to 7-membered lactone include β-propiolactone, β-butyrolactone, β-valerolactone, 3-methyl-β-propiolactone, γ- Butyrolactone, δ-valerolactone, 3-methyl-δ-valerolactone, 4-methyl-δ-valerolactone, δ-caprolactone, ε-caprolactone, 3-methyl-ε-caprolactone, 4-methyl-ε-caprolactone, 3 , 3,5-trimethyl-ε-caprolactone, 3,5,5-trimethyl-ε-caprolactone and 7-methyl-ε-caprolactone.
コポリマーは２元コポリマー又は３元コポリマーが好ましい。 The copolymer is preferably a binary copolymer or a ternary copolymer.
脂肪族ポリエステルとしては、ポリグリコール酸、ポリ乳酸等のポリ（α−ヒドロキシ酸）、ポリ−ε−カプロラクトン、ポリジオキサノン、ポリエチレンスクシネート、ポリエチレンアジペート、ポリブチレンスクシネート、ポリブチレンアジペート、ポリブチレンスクシネートアジペートなどが挙げられる。 Examples of the aliphatic polyester include poly (α-hydroxy acid) such as polyglycolic acid and polylactic acid, poly-ε-caprolactone, polydioxanone, polyethylene succinate, polyethylene adipate, polybutylene succinate, polybutylene adipate, and polybutylene. Examples include succinate adipate.
他の生体内吸収性ポリマーとしては、ポリ乳酸、ポリグリコール酸、ポリ-ε-カプロラクトン、グリコール酸と乳酸のコポリマー、乳酸と-ε-カプロラクトンのコポリマーなどが挙げられる。 Other bioabsorbable polymers include polylactic acid, polyglycolic acid, poly-ε-caprolactone, copolymers of glycolic acid and lactic acid, copolymers of lactic acid and -ε-caprolactone, and the like.
2-ピロリドンと他のモノマーとのコポリマーは、モル比で2-ピロリドン：他のモノマー＝１：９９〜９９：１、好ましくは１０：９０〜９８：２、より好ましくは５０：５０〜９５：５、さらに好ましくは７０：３０〜９０：１０程度である。2-ピロリドンとカプロラクトンのコポリマーは、ブロックコポリマーでもランダムコポリマーでもよく、ランダムコポリマーが好ましい。なお、他のモノマーは１種であってもよく(２元コポリマー)、２種(３元コポリマー)或いはそれ以上(多元コポリマー)であってもよい。
ポリアミド４のホモポリマーの数平均分子量（Ｍｎ）は、５０００〜１０００００程度、好ましくは７０００〜８００００程度、より好ましくは１００００〜５００００程度である。ポリアミド４のホモポリマーの重量平均分子量（Ｍｗ）は、１００００〜５０００００程度、好ましくは３００００〜４０００００程度、より好ましくは６００００〜２０００００程度である。ポリアミド４のコポリマーの数平均分子量（Ｍｎ）は、５０００〜１０００００程度、好ましくは８０００〜５００００程度、より好ましくは１００００〜２００００程度である。ポリアミド４のコポリマーの重量平均分子量（Ｍｗ）は、８０００〜２０００００程度、好ましくは１００００〜１０００００程度、より好ましくは１５０００〜３００００程度である。
Copolymers of 2-pyrrolidone and other monomers have a molar ratio of 2-pyrrolidone: other monomer = 1: 99 to 99: 1, preferably 10:90 to 98: 2, more preferably 50:50 to 95: 5, More preferably, it is about 70: 30-90: 10. The copolymer of 2-pyrrolidone and caprolactone may be a block copolymer or a random copolymer, and a random copolymer is preferred. The other monomer may be one kind (binary copolymer), two kinds (ternary copolymer) or more (multi-element copolymer).
The number average molecular weight (Mn) of the polyamide 4 homopolymer is about 5000 to 100,000, preferably about 7000 to 80000, and more preferably about 10000 to 50000. The weight average molecular weight (Mw) of the homopolymer of polyamide 4 is about 10,000 to 500,000, preferably about 30,000 to 400,000, and more preferably about 60000 to 200,000. The number average molecular weight (Mn) of the polyamide 4 copolymer is about 5,000 to 100,000, preferably about 8,000 to 50,000, and more preferably about 10,000 to 20,000. The weight average molecular weight (Mw) of the polyamide 4 copolymer is about 8,000 to 200,000, preferably about 10,000 to 100,000, and more preferably about 15,000 to 30,000.
数平均分子量及び重量平均分子量は、高速GPCシステム(東ソー社製、(HLC-8220GPCシステム))により、ポリメチルメタクリレートを標準物質として用いて測定することができる。ポリマー組成比は1HNMRにより算出できる。 The number average molecular weight and the weight average molecular weight can be measured with a high-speed GPC system (manufactured by Tosoh Corporation, (HLC-8220GPC system)) using polymethyl methacrylate as a standard substance. The polymer composition ratio can be calculated by 1 HNMR.
本発明の医療材料は長期間生体内に埋入しても異物反応や石灰化を惹起させず、生体適合性に優れ、かつ生体内で分解・吸収される。医療材料としては、例えばパッチ材、人工心臓弁、ステント、骨接合材、人工心膜、縫合糸、組織補填材、組織補強材、組織被覆材、組織再生用基材、細胞足場材料、組織補綴材、癒着防止材、クリップ、細胞シート、DDS基材などが挙げられる。 The medical material of the present invention does not cause a foreign body reaction or calcification even when embedded in a living body for a long period of time, is excellent in biocompatibility, and is decomposed and absorbed in the living body. Examples of medical materials include patch materials, artificial heart valves, stents, osteosynthesis materials, artificial pericardium, sutures, tissue filling materials, tissue reinforcement materials, tissue coating materials, tissue regeneration base materials, cell scaffold materials, tissue prosthesis Examples include materials, anti-adhesion materials, clips, cell sheets, and DDS substrates.
このような医療材料或いは生体内吸収性材料は、シート、フィルム、ロッド、プレート、スクリュー、ネット、織物、編物、不織布、多孔体、スポンジ、などの任意の形状であってもよい。 Such a medical material or a bioabsorbable material may have any shape such as a sheet, a film, a rod, a plate, a screw, a net, a woven fabric, a knitted fabric, a non-woven fabric, a porous body, and a sponge.
以下、実施例を挙げて本発明を説明するが、本発明はこれらの実施例に限定されるもの
ではない。
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.
調製例１：生体試料の調製方法
ポリアミド４、ポリアミド４のコポリマー（カプロラクトンとのコポリエステルアミド）を用いた。これらのポリマーを5〜10wt%トリフルオロエタノール溶液とし、20kVの電圧で電界紡糸し、不織布を得た。
Preparation Example 1: Preparation method of biological sample Polyamide 4 and a copolymer of polyamide 4 (copolyesteramide with caprolactone) were used. These polymers were made into 5-10 wt% trifluoroethanol solutions and electrospun at a voltage of 20 kV to obtain nonwoven fabrics.
試験例１：ラットを用いた生体内分解性試験
ラット（♂、8 週齢）の背面を切開し、皮下にポリアミド４、コポリエステルアミドおよびポリ乳酸を電界紡糸により作成した不織布として埋入した。一定期間後に試料を取り出し、溶剤で洗浄した後、ヘキサフルオロイソプロパノール(HFIP) による抽出にてポリマーを回収し、NMR のピーク強度からポリマーの残存量、分解率を求めた。
Test Example 1: Biodegradation test using rats Rats (♂, 8 weeks old) were incised on the back and embedded subcutaneously with polyamide 4, copolyesteramide and polylactic acid as a non-woven fabric made by electrospinning. After a certain period of time, the sample was taken out and washed with a solvent, and then the polymer was recovered by extraction with hexafluoroisopropanol (HFIP), and the residual amount of polymer and the decomposition rate were determined from the peak intensity of NMR.
埋入試料はポリアミド４と生分解性ポリエステルであるポリカプロラクトンとのコポリマーとしてランダム型3種とブロック性の強いコポリマー１つを用いた。 For the embedded sample, three types of random type and one highly blocky copolymer were used as a copolymer of polyamide 4 and polycaprolactone, which is a biodegradable polyester.
結果を表１に示す。 The results are shown in Table 1.
ポリ乳酸 は摘出後、メタノール洗浄、クロロホルムによる抽出で、その他のアミド系ポリマーはメタノール、クロロホルムで洗浄した後、HFIP で抽出して試料回収した。洗浄によって脂質成分が除去され、残存試料が回収された。No.5(ポリ乳酸)のNMR から、ポリ乳酸以外に大きく脂質成分が検出され、約2.4mol%分の夾雑脂質は平均C21.6 の脂肪酸のトリグリセリドと推定され、分子量が大きいため重量での夾雑率は26%と計算された。ポリアミド系はメタノール洗浄されているため、脂質シグナルは小さく、目的シグナルが明瞭で容易に解析できた。これらのNMR から重量保持率を定量した結果、No.1 のコポリマーの分解が速く、No.4 は比較的遅く、No.2 や3 では一定の分解を受けていることがわかった。また、コポリエステルアミドだけでなく、ポリアミド４(No.6)も生体内で生分解されることを明らかにした。 Polylactic acid was extracted, washed with methanol, and extracted with chloroform. Other amide polymers were washed with methanol and chloroform, and then extracted with HFIP to collect samples. The lipid component was removed by washing, and the remaining sample was collected. From the NMR of No. 5 (polylactic acid), a large lipid component was detected in addition to polylactic acid, and about 2.4 mol% of contaminated lipid was estimated to be an average C21.6 fatty acid triglyceride. The contamination rate was calculated as 26%. Since the polyamide system was washed with methanol, the lipid signal was small and the target signal was clear and could be analyzed easily. As a result of quantifying the weight retention from these NMR, it was found that the No. 1 copolymer decomposed quickly, No. 4 was relatively slow, and No. 2 and 3 were undergoing constant decomposition. It was also clarified that not only copolyesteramide but also polyamide 4 (No. 6) was biodegraded in vivo.
試験例１−２：ラットを用いた生体内分解性試験（経時変化）
三分岐型ポリアミド４、ランダム型コポリマー、ブロック型コポリマーのラットの背面皮下埋入試験の経時変化を調べたところ、いずれの試料も時間とともに重量が減少していくことがわかった(図１)。
Test Example 1-2: Biodegradability test using rats (change over time)
When time-dependent changes in the rat subcutaneous implantation test of the tribranched polyamide 4, random copolymer, and block copolymer were examined over time, it was found that the weight of each sample decreased with time (FIG. 1).
試験例１−３：ラットを用いた生体内分解性試験（炎症性について）
ポリアミド4とそのコポリマー、ポリ乳酸をラットの背面皮下に埋入し、８．５ヶ月後に埋入箇所を観察したところ、いずれの試料でも大きな炎症は観察されなかった(図２)。
Test Example 1-3: Biodegradability test using rats (for inflammation)
Polyamide 4 and its copolymer, polylactic acid were implanted subcutaneously in the back of the rat, and when the site of implantation was observed 8.5 months later, no significant inflammation was observed in any of the samples (FIG. 2).
試験例２：細胞毒性試験
方法：「医療機器の製造販売承認申請等に必要な生物学的安全性評価の基本的考え方について」に準拠して実施。
試料：ポリアミド４不織布
陰性対照材料：高密度ポリエチレンフィルム
陽性対照材料：zinc diethyldithiocarbamate（ZDEC）含有ポリウレタンフィルム
各0.1g/mL培地抽出液(24h) を100%として使用
細胞：チャイニーズ・ハムスター肺由来V79細胞培地で希釈した各々の濃度で6日間培養した後、コロニー数を計測。
Test example 2: Cytotoxicity test Method: Conducted in accordance with “Basic concept of biological safety evaluation required for application for manufacturing and marketing approval of medical devices”.
Sample: Polyamide 4 non-woven fabric Negative control material: High density polyethylene film
Positive control material: zinc diethyldithiocarbamate (ZDEC) -containing polyurethane film Each 0.1 g / mL medium extract (24 h) is used as 100%. Cells: After culturing at respective concentrations diluted with Chinese hamster lung-derived V79 cell medium for 6 days Count colonies.
ポリアミド４の生物学的安全性を調べるため、チャイニーズ・ハムスター肺由来のV79 細胞を用いるコロニー形成法における細胞毒性作用を、ポリアミド４培地抽出液、25〜100%の濃度範囲において検討した。その結果、表２に示すように、いずれの濃度においてもコロニー形成を阻害せず、ポリアミド４ はV79細胞のコロニー形成を阻害する細胞毒性作用はないことが示された。 In order to examine the biological safety of polyamide 4, the cytotoxic effect in the colony formation method using Chinese hamster lung-derived V79 cells was examined in a polyamide 4 medium extract, in a concentration range of 25 to 100%. As a result, as shown in Table 2, it was shown that polyamide 4 did not inhibit colony formation at any concentration, and polyamide 4 had no cytotoxic effect that inhibited V79 cell colony formation.
試験例３：変異原性試験
ポリアミド４の突然変異誘発性を調べるため、微生物を用いた復帰突然変異試験を行った。微生物としてネズミチフス菌4 株、大腸菌1 株を用い、代謝活性化有り無しの二条件、プレインキュベーション法（37℃、20分）で試験を行った。ポリアミド４試料はDMSO に懸濁し、37℃で48 時間抽出した抽出液を用いた。
Test Example 3: Mutagenicity test To examine the mutagenicity of polyamide 4, a reverse mutation test using microorganisms was performed. Using 4 strains of Salmonella typhimurium and 1 strain of Escherichia coli as microorganisms, the test was conducted under two conditions with and without metabolic activation under the preincubation method (37 ° C., 20 minutes). The polyamide 4 sample was suspended in DMSO and extracted at 37 ° C. for 48 hours.
ポリアミド４抽出液（5mg/mL)を段階的に希釈した試料を用いて試験を行った結果、ネガティブコントロール(DMSO)と比べると、ポリアミド４抽出液で処理するとコロニー数は最少で0.5、最多で1.5 倍となったが、それぞれのポジティブコントロールより多くなることはなく、復帰突然変異は誘発されなかった。Salmonella enterica NBRC 14194、S9 非存在条件ではポジティブコントロールでの変異誘発が見られなかったが、ポリアミド４によるコロニー数増加も無かった。以上の結果より、ポリアミド４に変異原性は無いことが示された。 As a result of testing using a sample obtained by serially diluting the polyamide 4 extract (5mg / mL), the number of colonies was 0.5 and the minimum when treated with the polyamide 4 extract compared to the negative control (DMSO). 1.5 times but no more than each positive control and no backmutation was induced. In the absence of Salmonella enterica NBRC 14194, S9, no mutagenesis was observed in the positive control, but there was no increase in the number of colonies due to polyamide 4. From the above results, it was shown that polyamide 4 is not mutagenic.
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| DE112016006538T5 (en) | 2016-03-02 | 2018-12-06 | Sumitomo Electric Industries Ltd. | Program update system, program update procedure and computer program |
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