JP2020130536A - Liquid polymeric compound composition and medical material - Google Patents
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Abstract
Description
本発明は、液状高分子化合物組成物および医療材料に関する。 The present invention relates to liquid polymeric compound compositions and medical materials.
生体の組織損傷による体液（血液、組織液など）漏出を防ぐ組織閉塞は、手術などの臨床上、重要な意味を持つ。損傷部からの体液漏出を効果的に抑えることは、患者の手術中の生命維持、術後の生活の質（ＱＯＬ）の向上につながる。 Tissue obstruction that prevents leakage of body fluid (blood, tissue fluid, etc.) due to tissue damage in the living body has clinical significance such as surgery. Effectively suppressing the leakage of fluid from the injured part leads to the maintenance of life during the operation of the patient and the improvement of the quality of life (QOL) after the operation.
臨床においては、止血が重要視される。その理由として、以下が挙げられる。
１．失血は死亡の大きな要因の１つであり、失血要因には、重篤な外傷、動脈瘤、食道や胃における潰瘍、および食道静脈瘤の破裂などがある。特に、緊急に止血治療を受けることができない場合には、死亡の可能性が高くなる。
２．手術時における出血は、手術における大きな懸念の一つで、出血により、全身感染症や臓器の機能不全が生じる。また、出血は術野を妨げるだけでなく、出血した血液の除去は手術の遅延につながる。
３．出血は、最小侵襲手術（腹腔鏡下手術など）を行っている場合でも問題となり、出血を十分に抑制できない場合、切開手術に変更せざるをえない場合もある。
In clinical practice, hemostasis is important. The reasons for this are as follows.
1. 1. Blood loss is one of the major causes of death, and blood loss factors include severe trauma, aneurysms, ulcers in the esophagus and stomach, and rupture of esophageal varices. In particular, death is more likely if hemostasis treatment is not available urgently.
2. 2. Bleeding during surgery is one of the major concerns in surgery, which causes systemic infections and organ dysfunction. In addition, bleeding not only interferes with the surgical field, but removal of bleeding blood leads to delayed surgery.
3. 3. Bleeding is a problem even when minimally invasive surgery (such as laparoscopic surgery) is performed, and if bleeding cannot be sufficiently suppressed, it may be necessary to change to open surgery.
既存の止血方法としては、以下が挙げられる。
１．出血部の血管に直に圧迫する方法（圧迫止血）。この止血法の欠点は、時間と手間がかかり圧力を維持しておく必要がある点、また患者に血腫ができる恐れがある点である。
２．その他の物理的手段による止血方法として、出血部近傍をクランプ、クリップする方法、出血部にプラグやスポンジのようなものを乗せる方法がある。これらの止血法の欠点は、多数の微小血管から出血している場合に扱いが困難である点である。
３．熱によって血液を凝固させ、出血している血管を焼灼する方法（電気メス）。この方法の欠点は、周囲組織を熱損傷させ患者への侵襲が大きい点、医療用器具が必要で専門性を要する点である（医療機関以外では使用できない）。
Existing hemostasis methods include:
1. 1. A method of directly compressing the blood vessels in the bleeding area (compression hemostasis). The disadvantages of this hemostasis method are that it takes time and effort to maintain pressure and that the patient may develop hematomas.
2. 2. Other methods of stopping bleeding by physical means include a method of clamping and clipping the vicinity of the bleeding part, and a method of placing something like a plug or sponge on the bleeding part. The disadvantage of these hemostatic methods is that they are difficult to handle when bleeding from a large number of microvessels.
3. 3. A method of coagulating blood with heat and cauterizing bleeding blood vessels (electric knife). The disadvantages of this method are that it causes thermal damage to surrounding tissues and is highly invasive to patients, and that medical equipment is required and requires specialization (it can only be used by medical institutions).
既存の止血材としては、以下が挙げられる。
１．アルギン酸
２．ゼラチンスポンジ
３．コラーゲン線維
４．フィブリン糊。
５．自己組織合成ペプチド
上記のうちコラーゲン線維とフィブリン糊が効果的な止血材として、臨床でしばしば利用されている。これらの欠点として、（１）ゼラチンとコラーゲン線維は動物性コラーゲン、フィブリン糊は血液製剤とウシ由来トロンビンを使用した動物由来製品であるため、感染症の危険性がある、（２）透明でないため術野の妨げとなる、点が挙げられる。
Examples of existing hemostatic materials include:
1. 1. Alginic acid 2. Gelatin sponge 3. Collagen fiber 4. Fibrin glue.
5. Self-Tissue Synthetic Peptides Of the above, collagen fibers and fibrin glue are often used clinically as effective hemostatic materials. These drawbacks are (1) gelatin and collagen fibers are animal collagen, and fibrin glue is an animal-derived product using blood products and bovine-derived thrombin, so there is a risk of infectious diseases, and (2) it is not transparent. There are some points that hinder the surgical field.
手術において患者の血液凝固能を人為的に低下させた、ヘパリン血状態にすることがある。人工心肺を使用する手術においては、血液凝固を抑えるためにヘパリンを使用する。人工心肺装置は生体にとって異物であり、血液をそのまま人工心肺装置へ流すと、すぐに血液が凝固し回路が詰まってしまうため、体外循環を行う前にヘパリンを血液に投与する。 In surgery, the patient's blood coagulation ability may be artificially reduced, resulting in a heparinous state. In surgery using a heart-lung machine, heparin is used to suppress blood coagulation. The heart-lung machine is a foreign substance to the living body, and when blood is flowed directly to the heart-lung machine, the blood immediately coagulates and the circuit is clogged. Therefore, heparin is administered to the blood before extracorporeal circulation.
コラーゲン線維、フィブリン糊は、生体の血液凝固系を利用して止血するため、ヘパリン血状態では、止血効果が低下する。止血効果が低下すると出血量が多くなるため輸血が必要になりやすく、また体外循環終了後の完全止血にも長時間を要する。したがって、ヘパリン血状態でも性能が低下しない血液凝固作用を利用しない止血材が求められている。 Collagen fibers and fibrin glue stop bleeding using the blood coagulation system of the living body, so that the hemostasis effect is reduced in the heparin blood state. When the hemostatic effect decreases, the amount of bleeding increases, so that blood transfusion is likely to be required, and it takes a long time to completely stop bleeding after the end of extracorporeal circulation. Therefore, there is a demand for a hemostatic material that does not utilize the blood coagulation action that does not deteriorate the performance even in the heparin blood state.
血管縫合は心臓・血管系手術だけでなく、一般的な腹腔内手術時にも必要になることがある。術後、血管縫合部からわずかな血液漏出があるため、それを持続的に抑える止血材が求められている。 Vascular sutures may be required not only during cardiac and vascular surgery, but also during general intra-abdominal surgery. Since there is a slight blood leakage from the sutured part of the blood vessel after the operation, a hemostatic material that continuously suppresses the leakage is required.
胆汁婁・膵液婁は、胆道系手術、膵炎や膵臓手術などによって胆汁、膵液が漏れ出し、他の臓器に悪影響を及ぼす症状のことである。現在、胆汁や膵液の漏出を効果的に抑え、かつ臨床使用可能な物質は知られておらず、安全かつ効果的に胆汁婁・膵液婁を防ぐ方法が求められている。 Bile and pancreatic juice are symptoms in which bile and pancreatic juice leak out due to biliary tract surgery, pancreatitis, pancreatic surgery, etc., and adversely affect other organs. Currently, there are no known substances that can effectively suppress the leakage of bile and pancreatic juice and that can be used clinically, and there is a need for a safe and effective method for preventing bile and pancreatic juice.
肺において、肺胞の嚢包が破れる自然気胸や、肋骨骨折やカテーテル穿刺等の外傷性気胸などにより、空気が漏出する病状が知られている。症状によっては自然治癒を待つしかなく、患部に上層するだけで肺組織と接着し、嚢包の穴を塞ぐことが可能な方法は、気胸を治療する手段として、簡便かつ安全性が高い方法の一つと考えらえる。 In the lung, there is known a condition in which air leaks due to spontaneous pneumothorax in which the alveolar sac is torn, or traumatic pneumothorax such as a rib fracture or catheter puncture. Depending on the symptom, there is no choice but to wait for spontaneous healing, and a method that can adhere to the lung tissue and close the hole in the pneumothorax simply by layering on the affected area is a simple and highly safe method for treating pneumothorax. Think of it as one.
内視鏡技術の発達により、病変部を内視鏡的に切除する技術が開発されてきている。特に食道、胃又は腸を含む消化管のポリープや早期がん（リンパ節転移がないと考えられている表層癌）等の病変部を内視鏡的に切除する手術法が確立されてきている。内視鏡的粘膜切除術では、一般的に病変部を含む粘膜下層に高張食塩水などを注入して病変部を隆起させ、切除部分を把持しながら電気メスなどにより病変部を含む組織の切除を行う。
当該手技において、病変部と固有筋層を引き離すために粘膜下層へ高張食塩水等の溶液を注入するが、食塩水等の粘性の低い溶液では病変部の隆起を手術中維持できないという問題点があり、患部の隆起を手術中維持可能な注入液が望まれている。
また、病変部切除部からの出血をトロンビンなどの血管収縮剤をカテーテルを利用して投与することで出血を抑制する方法が用いられるが、完全に出血を止める効果的な処置法は確立されておらず、切除後の出血を速やかに止める方法も同時に求められている。
With the development of endoscopic technology, a technique for endoscopically excising a lesion has been developed. In particular, surgical methods for endoscopically removing lesions such as polyps in the gastrointestinal tract including the esophagus, stomach or intestine and early stage cancer (superficial cancer that is considered to have no lymph node metastasis) have been established. .. In endoscopic mucosal resection, hypertonic saline is generally injected into the submucosa including the lesion to raise the lesion, and the tissue including the lesion is resected with an electric knife while grasping the resected part. I do.
In this procedure, a solution such as hypertonic saline is injected into the submucosa in order to separate the lesion from the muscularis propria, but there is a problem that the bulge of the lesion cannot be maintained during surgery with a low-viscosity solution such as saline. Therefore, an infusion solution capable of maintaining the bulge of the affected area during surgery is desired.
In addition, a method of suppressing bleeding by administering a vasoconstrictor such as thrombin using a catheter is used to bleed from the resected lesion, but an effective treatment method to completely stop the bleeding has been established. At the same time, there is a need for a method to promptly stop bleeding after excision.
カテーテル療法の発達により、腫瘍や筋腫等の血流支配をうける病変部へ流入する動脈を閉塞させることにより、腫瘍や筋腫等を死滅させる手術方法が確立されてきている。具体的には、肝臓脈閉塞術、子宮動脈閉塞術、脳動脈閉塞術等を挙げることができる。
当該手技において、動脈を閉塞させるために、異種動物から抽出されたコラーゲンやエチレンビニルアルコールなどの液体を注入するが、感染の危険性や生体毒性が懸念されている。そこで、感染の危険性がなく、かつ、生体毒性の低い注入液の開発が望まれている。
また、注入液は、抗癌剤や造影剤の添加が可能なものが求められている。
With the development of catheter therapy, surgical methods have been established to kill tumors and myomas by occluding the arteries that flow into lesions that are controlled by blood flow such as tumors and myomas. Specific examples thereof include liver pulse occlusion, uterine artery occlusion, and cerebral artery occlusion.
In this procedure, a liquid such as collagen or ethylene vinyl alcohol extracted from a different animal is injected in order to occlude an artery, but there are concerns about the risk of infection and biotoxicity. Therefore, it is desired to develop an injectable solution having no risk of infection and having low biotoxicity.
Further, the injection solution is required to be capable of adding an anticancer agent or a contrast agent.
そこで、近年、その物理的、化学的、生物学的性質から、新規マテリアルとして注目を浴びている高度に制御された自己組織化ペプチドがある。そのアミノ酸配列により、多数のペプチド分子が規則正しく並んだ自己会合体を形成する特性を有する。
自己組織化ペプチドは、電荷を帯びた親水性アミノ酸と電気的に中性な疎水性アミノ酸が交互に並び、正電荷と負電荷が交互に分布する構造をもち、生理的なｐＨと塩濃度においてβ構造をとる。
Therefore, in recent years, there is a highly controlled self-assembling peptide that has been attracting attention as a new material due to its physical, chemical, and biological properties. Due to its amino acid sequence, it has the property of forming a self-aggregate in which a large number of peptide molecules are regularly arranged.
The self-assembling peptide has a structure in which charged hydrophilic amino acids and electrically neutral hydrophobic amino acids are alternately arranged, and positive and negative charges are alternately distributed, and at physiological pH and salt concentration. It has a β structure.
自己組織化ペプチドの止血への応用では、肝臓切開部末端から持続的な血液漏出が認められ、完全止血ができていない。止血が不完全な理由は、自己組織化ペプチドゲルと組織の接着が不十分なためと推測される。したがって、自己組織化ペプチドの止血効果を臨床応用可能なレベルにまで引き出すためには、さらなる改良が必要である。 In the application of the self-assembled peptide to hemostasis, continuous blood leakage was observed from the end of the liver incision, and complete hemostasis was not achieved. It is presumed that the reason for incomplete hemostasis is insufficient adhesion between the self-assembled peptide gel and the tissue. Therefore, further improvements are needed to bring out the hemostatic effect of self-assembling peptides to clinically applicable levels.
また、伝統的な圧迫止血・縫合止血は、限界が指摘されている。現在市販されている止血剤や組織接着剤であるフィブリン糊は、ウイルス感染の危険性が高く、接着強度が弱いという問題点がある。
フィブリン糊と同様に臨床で用いられている、ゼラチンに架橋剤であるホルムアルデヒドやグルタルアルデヒドなどを加えてゲル化させたポリアミン-アルデヒド系は、血管閉塞等の後遺障害の可能性や低分子アルデヒド類の高い神経・組織障害性が指摘されており、決して満足のいくようなものではない。
In addition, the limitations of traditional compression hemostasis and suture hemostasis have been pointed out. Fibrin glue, which is a hemostatic agent or tissue adhesive currently on the market, has a problem that there is a high risk of virus infection and the adhesive strength is weak.
The polyamine-aldehyde system, which is used clinically like fibrin glue and is gelled by adding formaldehyde or glutaraldehyde, which are cross-linking agents, to gelatin has the possibility of residual disorders such as vascular occlusion and low molecular weight aldehydes. It has been pointed out that it has a high degree of neurological and tissue damage, and it is by no means satisfactory.
これらの問題点を克服すべく、多くの研究が実施されている。例えば、食品添加物を原料とするデキストランとε-ポリ-L-リジン（以下、単にε-PLLとも称する）を原料とする、架橋型シッフ塩基形成に基づく接着剤が研究されている（例えば、特許文献１および非特許文献１参照）。 Many studies have been conducted to overcome these problems. For example, adhesives based on crosslinked Schiff base formation using dextran and ε-poly-L-lysine (hereinafter, also simply referred to as ε-PLL) as raw materials of food additives are being studied (for example, See Patent Document 1 and Non-Patent Document 1).
また、強度的に強い接着剤としてはクエン酸を活性エステル化した誘導体とコラーゲン等のタンパクを接着成分とする組織接着剤も研究されている（例えば、特許文献２および非特許文献２参照）。
また、使用前にゼラチン溶液とトランスグルタミナーゼ溶液とを混合して使用する止血剤が知られている（例えば、特許文献３参照）。
Further, as a strong adhesive, a tissue adhesive containing a derivative obtained by active esterifying citric acid and a protein such as collagen as an adhesive component has also been studied (see, for example, Patent Document 2 and Non-Patent Document 2).
Further, there is known a hemostatic agent which is used by mixing a gelatin solution and a transglutaminase solution before use (see, for example, Patent Document 3).
しかしながら、特許文献１および非特許文献１に記載のε-PLL原料の接着剤では、ゲル強度が市販止血剤であるフィブリン糊よりも劣り、止血材としての強度不足が懸念されるという課題があった。
また、特許文献２および非特許文献２に記載の組織接着剤では、活性エステル化合物が化学的に不安定であり、水溶液での長期保存が不可能なため、使用直前に生体に悪影響を及ぼすリスクを有する溶媒に溶解させる必要性があり、さらに医師が外科手術などで緊急に使用するときにはすぐに使用できないために支障を来す可能性が高いという課題があった。
また、これらの接着剤は、非常に高価であるという課題があった。
特許文献３に記載の止血剤では、使用前にゼラチン溶液とトランスグルタミナーゼ溶液とを混合するため、すぐに使用できないという課題があった。
However, the adhesives used as ε-PLL raw materials described in Patent Document 1 and Non-Patent Document 1 have a problem that the gel strength is inferior to that of the commercially available hemostatic agent fibrin glue, and there is a concern that the strength as a hemostatic material is insufficient. It was.
Further, in the tissue adhesives described in Patent Document 2 and Non-Patent Document 2, the active ester compound is chemically unstable and cannot be stored for a long time in an aqueous solution, so that there is a risk of adversely affecting the living body immediately before use. There is a problem that it is necessary to dissolve it in a solvent containing an ester, and there is a high possibility that a problem will occur because it cannot be used immediately when a doctor uses it urgently in a surgical operation or the like.
In addition, these adhesives have a problem that they are very expensive.
The hemostatic agent described in Patent Document 3 has a problem that it cannot be used immediately because the gelatin solution and the transglutaminase solution are mixed before use.
本発明は、このような課題に着目してなされたもので、強度が大きく、安全性が高く、すぐに使用でき、安価に製造可能な液状高分子化合物組成物および医療材料を提供することを目的としている。 The present invention has been made in view of such problems, and is intended to provide a liquid polymer compound composition and a medical material having high strength, high safety, ready-to-use, and inexpensively produced. I am aiming.
前記目的を達成するため、本発明者らは鋭意検討を重ねた結果、ゼラチン、コラーゲンペプチド及び水溶性セルロースの１種または２種以上の組み合わせを多価アルコールまたはその誘導体の水溶液に溶解させたものが、従来ない、粘弾性がありながらも形状変化し、組織吸着性のあるものであることを発見し、本発明を完成するに至った。 As a result of diligent studies to achieve the above object, the present inventors have dissolved one or a combination of one or more of gelatin, collagen peptide and water-soluble cellulose in an aqueous solution of polyhydric alcohol or a derivative thereof. However, the present invention has been completed by discovering that it has a viscoelasticity but a shape change and a tissue-adsorbing property, which has never been seen before.
即ち、本発明に係る液状高分子化合物組成物は、多価アルコールまたはその誘導体および親水性高分子化合物を含むことを特徴とする。
本発明に係る液状高分子化合物組成物において、前記多価アルコールまたはその誘導体は重合度１〜１０のオリゴグリセリンまたはその誘導体から成ることが好ましい。
That is, the liquid polymer compound composition according to the present invention is characterized by containing a polyhydric alcohol or a derivative thereof and a hydrophilic polymer compound.
In the liquid polymer compound composition according to the present invention, the polyhydric alcohol or its derivative is preferably composed of oligoglycerin having a degree of polymerization of 1 to 10 or a derivative thereof.
前記親水性高分子化合物は分子量２，０００以上１００，０００以下のゼラチン、コラーゲンペプチド及び水溶性セルロースの１種または２種以上の組み合わせから成ることが好ましい。 The hydrophilic polymer compound preferably comprises one or a combination of two or more of gelatin, collagen peptide and water-soluble cellulose having a molecular weight of 2,000 or more and 100,000 or less.
本発明に係る液状高分子化合物組成物は、全重量に対し、前記多価アルコールまたはその誘導体４８〜６８重量％および前記親水性高分子化合物２５〜４８重量％を含むことが好ましい。 The liquid polymer compound composition according to the present invention preferably contains 48 to 68% by weight of the polyhydric alcohol or a derivative thereof and 25 to 48% by weight of the hydrophilic polymer compound with respect to the total weight.
本発明に係る液状高分子化合物組成物は、分子量２，０００以上1００,０００以下の親水性高分子化合物を多価アルコールまたはその誘導体の水溶液に溶解させることにより製造することができる。 The liquid polymer compound composition according to the present invention can be produced by dissolving a hydrophilic polymer compound having a molecular weight of 2,000 or more and 1,000,000 or less in an aqueous solution of a polyhydric alcohol or a derivative thereof.
本発明に係る医療材料は、前述の液状高分子化合物組成物を含むことを特徴とする。
本発明に係る医療材料としては、例えば、生体用組織接着剤、止血剤、細胞保存液、臓器保存液、人工軟膏、歯槽骨再建剤、生体組織癒着防止剤、粘膜隆起剤または後出血防止剤が挙げられる。本発明に係る医療材料は、シート材の片面に本発明に係る液状高分子化合物組成物が付着されていてもよい。
The medical material according to the present invention is characterized by containing the above-mentioned liquid polymer compound composition.
Examples of the medical material according to the present invention include a biological tissue adhesive, a hemostatic agent, a cell preservation solution, an organ preservation solution, an artificial ointment, an alveolar bone reconstruction agent, a biological tissue adhesion inhibitor, a mucosal ridge agent or a post-bleeding inhibitor. Can be mentioned. The medical material according to the present invention may have the liquid polymer compound composition according to the present invention adhered to one side of the sheet material.
本発明によれば、強度が大きく、安全性が高く、すぐに使用でき、安価に製造可能な液状高分子化合物組成物および医療材料を提供することができる。 According to the present invention, it is possible to provide a liquid polymer compound composition and a medical material having high strength, high safety, ready-to-use, and inexpensively produced.
以下、本発明の実施の形態の液状高分子化合物組成物および医療材料について説明する。
本発明の実施の形態の液状高分子化合物組成物は、多価アルコールまたはその誘導体および親水性高分子化合物を含む。
Hereinafter, the liquid polymer compound composition and the medical material according to the embodiment of the present invention will be described.
The liquid polymer compound composition of the embodiment of the present invention contains a polyhydric alcohol or a derivative thereof and a hydrophilic polymer compound.
多価アルコールまたはその誘導体は、水酸基を有しながらも簡単に気化してしまわないよう、沸点が１００℃以上のもの、より好ましくは１５０℃以上のもの、さらに好ましくは１７０℃以上のものが好ましい。多価アルコールまたはその誘導体としては、例えば、グリセリン、プロピレングリコール、ジグリセリン、トリグリセリン、テトラグリセリン、ペンタグリセリン、ヘキサグリセリン、ヘプタグリセリン、オクタグリセリン、ナノグリセリン、デカグリセリンおよびそれらの脂肪酸誘導体が挙げられる。 The polyhydric alcohol or its derivative preferably has a boiling point of 100 ° C. or higher, more preferably 150 ° C. or higher, still more preferably 170 ° C. or higher so that it does not easily vaporize even though it has a hydroxyl group. .. Examples of the polyhydric alcohol or a derivative thereof include glycerin, propylene glycol, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, octaglycerin, nanoglycerin, decaglycerin and fatty acid derivatives thereof. ..
但し、グリセリンの脂肪酸エステルの鎖長が長くなればなるほど、水溶性が下がることから、鎖長は短いほうが好ましい、グリセリンの脂肪酸エステルの鎖長は、炭素数が１８以下、より好ましくは１４以下、さらに好ましくは１２以下が好ましい。多価アルコールまたはその誘導体は、重合度１〜１０のオリゴグリセリンまたはその誘導体から成ることが特に好ましい。 However, the longer the chain length of the glycerin fatty acid ester, the lower the water solubility. Therefore, the shorter the chain length is preferable. The chain length of the glycerin fatty acid ester has 18 or less carbon atoms, more preferably 14 or less. More preferably, it is 12 or less. The polyhydric alcohol or its derivative is particularly preferably composed of oligoglycerin having a degree of polymerization of 1 to 10 or a derivative thereof.
親水性高分子化合物としては、コラーゲン、ゼラチン、コラーゲンペプチド、ヒアルロン酸、アルギン酸、キチン、キトサン、セルロース、ヒドロキシプロピルセルロース、化工でんぷんなどを例示することができる。特に、親水性高分子化合物として、水に溶解させることができ、加工性に優れることから、ゼラチン、コラーゲンペプチド及び水溶性セルロースの１種または２種以上の組み合わせを用いることが好ましく、さらに、抗原性を低減した分子量２，０００以上１００，０００以下のゼラチンもしくはコラーゲンペプチド、または、１０００，０００以下のヒドロキシプロピルセルロースから成ることがより好ましく、分子量３０，０００以上１００，０００以下が特に好ましい。 Examples of the hydrophilic polymer compound include collagen, gelatin, collagen peptide, hyaluronic acid, alginic acid, chitin, chitosan, cellulose, hydroxypropyl cellulose, and chemical starch. In particular, as the hydrophilic polymer compound, since it can be dissolved in water and has excellent processability, it is preferable to use one or more combinations of gelatin, collagen peptide and water-soluble cellulose, and further, an antigen. It is more preferably composed of gelatin or collagen peptide having a reduced molecular weight of 2,000 or more and 100,000 or less, or hydroxypropyl cellulose having a molecular weight of 1,000,000 or less, and particularly preferably 30,000 or more and 100,000 or less.
本発明の実施の形態の液状高分子化合物組成物は、全重量に対し、多価アルコールまたはその誘導体４８〜６８重量％、親水性高分子化合物２５〜４８重量％を含むことが好ましい。この配合比率の場合、本発明の実施の形態の液状高分子化合物組成物は、粘弾性を有しながら、変形性を有し、臓器への高い組織接着性を有する。 The liquid polymer compound composition of the embodiment of the present invention preferably contains 48 to 68% by weight of a polyhydric alcohol or a derivative thereof and 25 to 48% by weight of a hydrophilic polymer compound based on the total weight. In the case of this blending ratio, the liquid polymer compound composition of the embodiment of the present invention has viscoelasticity, deformability, and high tissue adhesion to organs.
分子量２，０００以上１００,０００以下の親水性高分子化合物のみの場合、透明性が低く、組織接着性は低い。それに対し、多価アルコールまたはその誘導体と分子量２，０００以上３００,０００以下の親水性高分子化合物とを含む液状高分子化合物組成物は、多価アルコールまたはその誘導体を含ませることにより、透明性が上がり、変形性を維持しながら、ゲル強度が格段に向上する。特に、親水性高分子化合物がコラーゲン、ゼラチンまたはコラーゲンペプチドから成る場合、その効果は顕著である。多価アルコールまたはその誘導体と、ゼラチンまたはコラーゲンペプチドとの組成物は、医療材料として用いたとき、生体組織の水分を吸水し、ヒドロゲル状になり、高い密着、圧着効果を奏する。 In the case of only a hydrophilic polymer compound having a molecular weight of 2,000 or more and 100,000 or less, the transparency is low and the tissue adhesiveness is low. On the other hand, a liquid polymer compound composition containing a polyhydric alcohol or a derivative thereof and a hydrophilic polymer compound having a molecular weight of 2,000 or more and 300,000 or less is transparent by containing the polyhydric alcohol or a derivative thereof. The gel strength is significantly improved while maintaining the deformability. In particular, when the hydrophilic polymer compound consists of collagen, gelatin or collagen peptide, the effect is remarkable. When the composition of polyhydric alcohol or its derivative and gelatin or collagen peptide is used as a medical material, it absorbs water from living tissue and becomes hydrogel-like, and exhibits high adhesion and pressure-bonding effect.
本発明の実施の形態の液状高分子化合物組成物は、分子量２，０００以上３００,０００以下の親水性高分子化合物を多価アルコールまたはその誘導体の水溶液に溶解させることにより製造することができる。 The liquid polymer compound composition of the embodiment of the present invention can be produced by dissolving a hydrophilic polymer compound having a molecular weight of 2,000 or more and 300,000 or less in an aqueous solution of a polyhydric alcohol or a derivative thereof.
本発明の実施の形態の医療材料は、前述の液状高分子化合物組成物を含む。本発明の実施の形態の医療材料は、液状高分子化合物組成物により、粘弾性を有しながら、変形性を維持し、組織接着性を有する。本発明の実施の形態の医療材料には、腫瘍マーカーや医療用蛍光・発行剤、診断用金属、量子ドット、賦形剤、蛋白質、キレート剤、乳化剤、着色剤、その他の医薬部外品が混合されてもよい。医療材料として、生体用組織接着剤、止血剤、細胞保存液、臓器保存液、人工軟膏、歯槽骨再建剤、生体組織癒着防止剤、粘膜隆起剤および後出血防止剤などが挙げられる。
本発明の実施の形態の医療材料は、生体組織に付着させて用いることができる。生体組織への付着方法としては、シリンジによる投入が挙げられる。本発明の実施の形態の医療材料の上にシート材その他の被覆材が張り付けられてもよい。
The medical material of the embodiment of the present invention includes the above-mentioned liquid polymer compound composition. The medical material according to the embodiment of the present invention has viscoelasticity, maintains deformability, and has tissue adhesiveness due to the liquid polymer compound composition. Medical materials according to embodiments of the present invention include tumor markers, medical fluorescent / issuing agents, diagnostic metals, quantum dots, excipients, proteins, chelating agents, emulsifiers, colorants, and other non-pharmaceutical products. It may be mixed. Examples of medical materials include biological tissue adhesives, hemostatic agents, cell preservation solutions, organ preservation solutions, artificial ointments, alveolar bone reconstruction agents, biological tissue adhesion inhibitors, mucosal ridge agents and post-bleeding inhibitors.
The medical material of the embodiment of the present invention can be used by adhering to a living tissue. Examples of the method of adhering to living tissue include injection with a syringe. A sheet material or other covering material may be attached on the medical material according to the embodiment of the present invention.
本発明の実施の形態の医療材料は、シート材の片面に前述の液状高分子化合物組成物が付着されて成っていてもよい。シート材は、多価アルコールまたはその誘導体と分子量２，０００以上３００,０００以下の架橋した親水性高分子化合物とを含むシート状の天然高分子化合物組成物から成ることが好ましい。その天然高分子化合物組成物は、架橋剤としてトランスグルタミナーゼを含むことが好ましい。親水性高分子化合物は、分子量２，０００以上１００，０００以下のゼラチンまたはコラーゲンペプチドから成ることが好ましい。また、その多価アルコールまたはその誘導体は、重合度１〜１０のオリゴグリセリンまたはその誘導体から成ることが好ましい。特に、天然高分子化合物組成物のシート材は、架橋剤を含む点を除き、付着される液状高分子化合物組成物と同一の成分、配合から成ることが好ましい。 The medical material according to the embodiment of the present invention may be formed by adhering the above-mentioned liquid polymer compound composition to one side of a sheet material. The sheet material is preferably composed of a sheet-like natural polymer compound composition containing a polyhydric alcohol or a derivative thereof and a crosslinked hydrophilic polymer compound having a molecular weight of 2,000 or more and 300,000 or less. The natural polymer compound composition preferably contains transglutaminase as a cross-linking agent. The hydrophilic polymer compound preferably consists of gelatin or collagen peptide having a molecular weight of 2,000 or more and 100,000 or less. Further, the polyhydric alcohol or a derivative thereof preferably comprises oligoglycerin having a degree of polymerization of 1 to 10 or a derivative thereof. In particular, the sheet material of the natural polymer compound composition preferably has the same components and formulations as the liquid polymer compound composition to be adhered, except that it contains a cross-linking agent.
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。 Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.
（実施例１）
グリセリン：ゼラチン粉末(ニッピ社製)：水の重量比が４：１：５の液状高分子化合物組成物を作製した。ゼラチン粉末は、分子量８，０００のものを用いた。液状高分子化合物組成物は、それらの材料を混合、撹拌し、グリセリンおよびゼラチン粉末を水に溶解させて作製した。作製した液状高分子化合物組成物は、止血剤として用いられる。
(Example 1)
A liquid polymer compound composition having a weight ratio of glycerin: gelatin powder (manufactured by Nippi): water of 4: 1: 5 was prepared. A gelatin powder having a molecular weight of 8,000 was used. The liquid polymer compound composition was prepared by mixing and stirring these materials and dissolving glycerin and gelatin powder in water. The prepared liquid polymer compound composition is used as a hemostatic agent.
（実施例２）
グリセリン：ゼラチン粉末(ニッピ社製)：水の重量比が４：１：５の液状高分子化合物組成物を作製した。ゼラチン粉末は、分子量１００，０００のものを用いた。液状高分子化合物組成物は、それらの材料を混合、撹拌し、グリセリンおよびゼラチン粉末を水に溶解させて作製した。作製した液状高分子化合物組成物は、止血剤として用いられる。
(Example 2)
A liquid polymer compound composition having a weight ratio of glycerin: gelatin powder (manufactured by Nippi): water of 4: 1: 5 was prepared. A gelatin powder having a molecular weight of 100,000 was used. The liquid polymer compound composition was prepared by mixing and stirring these materials and dissolving glycerin and gelatin powder in water. The prepared liquid polymer compound composition is used as a hemostatic agent.
（実施例３）
止血剤の液状高分子化合物組成物を作製した。グリセリン：分子量３，０００のゼラチン粉末(ニッピ社製)：水の重量比が６：２：４の水溶液を作製し、溶液をシャーレに流延し、−８０℃の冷凍庫に６時間入れてゼラチン水溶液を凍結させた後、凍結乾燥機中で４８時間、凍結乾燥処理し、水で５０％希釈して液状高分子化合物組成物の止血剤を作製した。止血剤は、止血部位に投入した後、止血部位に広げて用いられる。
(Example 3)
A liquid polymer compound composition of a hemostatic agent was prepared. Glycerin: gelatin powder with a molecular weight of 3,000 (manufactured by Nippi): Prepare an aqueous solution with a weight ratio of water of 6: 2: 4, cast the solution on a petri dish, and put it in a freezer at -80 ° C for 6 hours to gelatin. After freezing the aqueous solution, it was freeze-dried in a freeze-dryer for 48 hours and diluted 50% with water to prepare a hemostatic agent for a liquid polymer compound composition. The hemostatic agent is applied to the hemostatic site and then spread over the hemostatic site.
（実施例４）
ゼラチン粉末(ニッピ社製)の代わりに、ゼラチン粉末(ニッピ社製)とヒドロキシプロピルセルロース（商品名「メトセル」、ダウケミカル社製）とを２：３の重量比で混合した点を除き、実施例１と同様の方法で液状高分子化合物組成物の止血剤を作製した。
(Example 4)
Conducted except that gelatin powder (manufactured by Nippi) and hydroxypropyl cellulose (trade name "Metcell", manufactured by Dow Chemical Co., Ltd.) were mixed in a weight ratio of 2: 3 instead of gelatin powder (manufactured by Nippi). A hemostatic agent of a liquid polymer compound composition was prepared in the same manner as in Example 1.
（実施例５）
グリセリンの代わりに、グリセリンとデカグリセリンモノラウリン酸エステル（三菱ケミカルフーズ社製）を９：１の重量比で混合した点を除き、実施例１と同様の方法で液状高分子化合物組成物の止血剤を作製した。
(Example 5)
A hemostatic agent for a liquid polymer compound composition in the same manner as in Example 1 except that glycerin and decaglycerin monolauric acid ester (manufactured by Mitsubishi Chemical Foods Co., Ltd.) were mixed in place of glycerin in a weight ratio of 9: 1. Was produced.
（実施例６）
グリセリン：ゼラチン粉末(ニッピ社製)：トランスグルタミナーゼ（味の素社製）を２：２：０．０１の組成重量比で準備した。ゼラチン粉末は、分子量３０，０００以上３００，０００以下のものを用いた。トランスグルタミナーゼは、酵素活性８６Ｕ／ｇのものを用いた。グリセリン：ゼラチン粉末：水の重量比が２：２：６の水溶液を作製し、この水溶液を２５℃に保ち、トランスグルタミナーゼを添加した。この混合水溶液を冷蔵庫に入れ、５℃で一昼夜反応させた。その後、ホモミキサーを用いて、回転数１８０００ｒｐｍで１０分間撹拌し、均質化した。撹拌後の溶液をシャーレに流延し、−８０℃の冷凍庫に６時間入れてゼラチン水溶液を凍結させた後、凍結乾燥機中で４８時間、凍結乾燥処理した。こうして、厚さ３５５μｍのシート状に成形された架橋ゼラチン多孔質体から成る天然高分子化合物組成物の止血材を作製した。
そのシート状止血材の片面に実施例１の止血剤を塗布し、層状止血材を作製した。
(Example 6)
Glycerin: gelatin powder (manufactured by Nippi): transglutaminase (manufactured by Ajinomoto Co., Inc.) was prepared at a composition weight ratio of 2: 2: 0.01. As the gelatin powder, a gelatin powder having a molecular weight of 30,000 or more and 300,000 or less was used. As the transglutaminase, one having an enzyme activity of 86 U / g was used. An aqueous solution having a weight ratio of glycerin: gelatin powder: water of 2: 2: 6 was prepared, the aqueous solution was kept at 25 ° C., and transglutaminase was added. This mixed aqueous solution was placed in a refrigerator and reacted at 5 ° C. for 24 hours. Then, using a homomixer, the mixture was stirred at a rotation speed of 18,000 rpm for 10 minutes to homogenize. The stirred solution was poured into a petri dish, placed in a freezer at −80 ° C. for 6 hours to freeze the gelatin aqueous solution, and then freeze-dried in a freeze-dryer for 48 hours. In this way, a hemostatic material of a natural polymer compound composition composed of a crosslinked gelatin porous body formed into a sheet having a thickness of 355 μm was prepared.
The hemostatic agent of Example 1 was applied to one side of the sheet-shaped hemostatic material to prepare a layered hemostatic material.
（比較例１）
グリセリンのみから成る止血剤を準備した。
（比較例２）
分子量３００，０００の１０％ゼラチン水溶液のみから成る止血剤を準備した。
(Comparative Example 1)
A hemostatic agent consisting only of glycerin was prepared.
(Comparative Example 2)
A hemostatic agent consisting only of a 10% gelatin aqueous solution having a molecular weight of 300,000 was prepared.
[止血試験１]
ラット肝臓生検トレパンモデルを用いて、実施例１〜３の止血剤による止血効果を確認した。
ラット肝臓生検トレパンモデルには、以下のラットを用いた。
ラット
Jcl/Wister♂
5W:110〜130g
[Hemostasis test 1]
Using a rat liver biopsy trepan model, the hemostatic effect of the hemostatic agents of Examples 1 to 3 was confirmed.
The following rats were used as the rat liver biopsy trepan model.
Rat
Jcl / Wister ♂
5W: 110-130g
ラット肝臓部位を３ｃｍ生検トレパンでくり抜き、出血することを確認し、これを出血モデルとした。
実施例１〜５および比較例１，２の各止血剤をシリンジで各ラットの出血部位にそれぞれ等量投入し、止血状態を観察した。また、止血剤および止血材を用いない未処置の出血モデルについて、止血状態を観察した。
止血剤を投入から１分後、各止血剤をふき取り、止血状態を観察した。
その結果を表１に示す。
The rat liver site was hollowed out with a 3 cm biopsy trepan, and it was confirmed that bleeding occurred, and this was used as a bleeding model.
Equal amounts of the hemostatic agents of Examples 1 to 5 and Comparative Examples 1 and 2 were added to the bleeding site of each rat with a syringe, and the hemostatic state was observed. In addition, the hemostatic state was observed for an untreated bleeding model that did not use a hemostatic agent or a hemostatic material.
One minute after the hemostatic agent was added, each hemostatic agent was wiped off and the hemostatic state was observed.
The results are shown in Table 1.
比較例１では血液といっしょに止血剤が流れてしまった。比較例２では出血部位の一部が固まって、そのわきから出血が止まらなくなった。表１に示すように、比較例１，２では止血効果はなかった。これに対し、実施例１〜３では止血効果が確認できた。 In Comparative Example 1, the hemostatic agent flowed along with the blood. In Comparative Example 2, a part of the bleeding site was solidified, and the bleeding did not stop from the side. As shown in Table 1, there was no hemostatic effect in Comparative Examples 1 and 2. On the other hand, in Examples 1 to 3, a hemostatic effect was confirmed.
[止血試験２]
ラット脊髄静脈を用いて、実施例１〜５の止血剤による止血効果を確認した。
以下のラットを用いた。
ラット
Jcl/Wister♂
5W:110〜130g
[Hemostasis test 2]
Using rat spinal veins, the hemostatic effect of the hemostatic agents of Examples 1 to 5 was confirmed.
The following rats were used.
Rat
Jcl / Wister ♂
5W: 110-130g
ラット脊髄静脈を２２Ｇのシリンジで突き刺し、出血することを確認し、これを出血モデルとした。
実施例１〜５および比較例１，２の各止血剤をシリンジ２２Gで各ラットの出血部位に投入し、止血状態を観察した。各止血剤の投入量は、止血試験１で用いた量を１とした場合の比率で示した。各止血剤の投入は、止血するか、または比率１０に達するまで行った。また、止血剤および止血材を用いない未処置の出血モデルについて、止血状態を観察した。
その結果を表２に示す。
The rat spinal vein was pierced with a 22G syringe, and bleeding was confirmed, which was used as a bleeding model.
The hemostatic agents of Examples 1 to 5 and Comparative Examples 1 and 2 were injected into the bleeding site of each rat with a syringe 22G, and the hemostatic state was observed. The amount of each hemostatic agent added is shown as a ratio when the amount used in the hemostatic test 1 is 1. Each hemostatic agent was added until the hemostatic was stopped or the ratio reached 10. In addition, the hemostatic state was observed for an untreated bleeding model that did not use a hemostatic agent or a hemostatic material.
The results are shown in Table 2.
表２に示すように、比較例１では、比率１０に達するまで投入しても全く止血できなかった。比較例２では、比率１０に達するまで投入しても止血剤の横のいくつもの場所から血液が漏れて、止血できなかった。このように、比較例１，２では止血効果はなかった。これに対し、実施例１〜５は止血効果が確認できた。特に、実施例５では、短時間でしっかり止血効果が確認できた。 As shown in Table 2, in Comparative Example 1, hemostasis could not be stopped at all even if the mixture was added until the ratio reached 10. In Comparative Example 2, even if the mixture was added until the ratio reached 10, blood leaked from several places next to the hemostatic agent, and the hemostatic could not be stopped. As described above, there was no hemostatic effect in Comparative Examples 1 and 2. On the other hand, the hemostatic effect was confirmed in Examples 1 to 5. In particular, in Example 5, the hemostatic effect was confirmed firmly in a short time.
[止血試験３]
ラット肝臓部位を22Gのシリンジで突き刺し、出血することを確認し、これを出血モデルとした。
実施例１で使用した液体止血剤を用いて２種類の方法で止血し、止血状態を確認した。止血剤を投入から１分後、各止血剤をふき取り、止血状態を観察した。
（方法１）
出血部位に実施例１の止血剤を投入し、その上に実施例６のシート状止血材をかぶせて、止血状態を観察した。
（方法２）
実施例１の止血剤をシート状止血材に塗布して成る実施例６の層状止血材を、出血部位にかぶせ、止血状態を観察した。
（比較例３）
出血部位にシート状止血材（商品名「インテグラン」、日本臓器製薬製）をかぶせて、止血状態を観察した。
その結果を表３に示す。
[Hemostasis test 3]
The rat liver site was pierced with a 22G syringe, and bleeding was confirmed, which was used as a bleeding model.
Hemostasis was performed by two methods using the liquid hemostatic agent used in Example 1, and the hemostatic state was confirmed. One minute after the hemostatic agent was added, each hemostatic agent was wiped off and the hemostatic state was observed.
(Method 1)
The hemostatic agent of Example 1 was added to the bleeding site, and the sheet-shaped hemostatic material of Example 6 was placed on the hemostatic agent, and the hemostatic state was observed.
(Method 2)
The layered hemostatic material of Example 6 formed by applying the hemostatic agent of Example 1 to the sheet-shaped hemostatic material was put on the bleeding site, and the hemostatic state was observed.
(Comparative Example 3)
The bleeding site was covered with a sheet-like hemostatic material (trade name "Integra", manufactured by Nippon Zoki Pharmaceutical Co., Ltd.), and the hemostatic state was observed.
The results are shown in Table 3.
比較例３は止血したが、シートから血液が染み出ていたのに対し、方法１，２では止血効果が確認できた。方法１，２は、止血試験１の実施例1〜５以上に、止血効果が大きかった。 Although hemostasis was performed in Comparative Example 3, blood exuded from the sheet, whereas methods 1 and 2 confirmed the hemostasis effect. Methods 1 and 2 had a greater hemostatic effect than Examples 1 to 5 of the hemostatic test 1.
[止血試験４]
マウス肝臓注射針穿孔モデルを用いて、実施例１〜３の止血剤および実施例６のシート状止血材の組合せによる止血効果を確認した。
マウス肝臓注射針穿孔モデルには、以下のマウスを用いた。
マウス
BALB/CAJCl♂
5W:20〜22g
[Hemostasis test 4]
Using a mouse liver injection needle perforation model, the hemostatic effect of the combination of the hemostatic agents of Examples 1 to 3 and the sheet-shaped hemostatic material of Example 6 was confirmed.
The following mice were used as a mouse liver injection needle perforation model.
mouse
BALB / CAJCl♂
5W: 20-22g
マウス肝臓部位を22Gのシリンジで突き刺し、出血することを確認し、これを出血モデルとした。
実施例１〜３の各止血剤をシリンジで各マウスの出血部位に投入した。その後、止血部位に実施例６のシート状止血材を貼り、止血状態を観察した。比較のため、比較例３のように、止血部位にシート状止血材（商品名「インテグラン」、日本臓器製薬製）をかぶせて、止血状態を観察した。また、止血剤および止血材を用いない未処置の出血モデルについて、止血状態を観察した。
止血材を貼ってから１分後、各止血剤と止血材をふき取り、止血状態を観察した。
その結果を表４に示す。
The mouse liver site was pierced with a 22G syringe, and bleeding was confirmed, which was used as a bleeding model.
Each hemostatic agent of Examples 1 to 3 was injected into the bleeding site of each mouse with a syringe. Then, the sheet-shaped hemostatic material of Example 6 was attached to the hemostatic site, and the hemostatic state was observed. For comparison, as in Comparative Example 3, a sheet-shaped hemostatic material (trade name "Integra", manufactured by Nippon Zoki Pharmaceutical Co., Ltd.) was placed on the hemostatic site, and the hemostatic state was observed. In addition, the hemostatic state was observed for an untreated bleeding model that did not use a hemostatic agent or a hemostatic material.
One minute after applying the hemostatic material, each hemostatic agent and the hemostatic material were wiped off, and the hemostatic state was observed.
The results are shown in Table 4.
比較例３では血液といっしょに止血剤が流れてしまい、表４に示すように止血効果はなかった。これに対し、実施例１〜３では止血効果が確認できた。実施例１〜３の止血剤とともにシート状止血材を用いた圧迫止血の場合には、特に止血効果が大きかった。 In Comparative Example 3, the hemostatic agent flowed together with the blood, and as shown in Table 4, there was no hemostatic effect. On the other hand, in Examples 1 to 3, a hemostatic effect was confirmed. In the case of compression hemostasis using a sheet-shaped hemostatic material together with the hemostatic agents of Examples 1 to 3, the hemostatic effect was particularly large.
Claims (7)
A medical material characterized in that the liquid polymer compound composition according to any one of claims 1 to 4 is adhered to one side of a sheet material.
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| WO2022024399A1 (en) | 2020-07-31 | 2022-02-03 | 住友ベークライト株式会社 | Powder coating material |
| US11951229B2 (en) | 2020-08-20 | 2024-04-09 | Aobakasei Kabushiki Kaisha | Liquid hemostatic medical material |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022024399A1 (en) | 2020-07-31 | 2022-02-03 | 住友ベークライト株式会社 | Powder coating material |
| US11951229B2 (en) | 2020-08-20 | 2024-04-09 | Aobakasei Kabushiki Kaisha | Liquid hemostatic medical material |
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| JP7389418B2 (en) | 2023-11-30 |
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