JP2012130672A - Injectable paste-like composition and bone or tooth filler comprising the same - Google Patents
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Abstract
Description
本発明は、注入が可能なペースト状組成物及びそれから成る骨又は歯充填材に関する。 The present invention relates to an injectable paste-like composition and a bone or tooth filler comprising the same.
近年、我が国の高齢者人口は顕著な増加傾向を示している。これに伴い、近い将来において高齢者に発症が多く見られる骨粗鬆症の罹患率上昇が予想される。骨粗鬆症が発症すると骨の形成と吸収のバランスが崩れ、骨密度が低下する。そのため骨組織が荷重に対し脆弱になり、圧迫骨折が発症しやすくなる。例えば、上半身の姿勢を支える脊椎においては椎体圧迫骨折が発症した場合、脊椎の前彎化やback painを引き起こし、QOL (Quality of Life)低下を引き起こす。 In recent years, the elderly population in Japan has shown a marked increase. Along with this, an increase in the prevalence of osteoporosis, which often occurs in elderly people in the near future, is expected. When osteoporosis develops, the balance between bone formation and resorption is lost, and bone density decreases. As a result, the bone tissue becomes vulnerable to the load, and compression fracture is likely to occur. For example, when a vertebral body compression fracture occurs in the spine that supports the posture of the upper body, it causes anterior vertebralization and back pain, resulting in a reduction in quality of life (QOL).
椎体圧迫骨折の治療法として骨セメントによる経皮的椎体形成術(Vertebroplasty, Kyphoplasty)が選択され、良好な術後成績が得られている。これまでは骨セメントとしてPoly(methyl methacrylate)(PMMA)が用いられてきたが、硬化反応時に発生する重合熱による周囲組織の壊死、新生骨との直接結合しないこと、隣接椎体骨折などが問題視され、それに代わる新たな骨セメントとしてリン酸カルシウムセメントの研究開発が進められている。 Percutaneous vertebroplasty (Vertebroplasty, Kyphoplasty) with bone cement has been selected as a treatment method for vertebral body compression fractures, and good postoperative results have been obtained. Until now, poly (methyl methacrylate) (PMMA) has been used as a bone cement, but there are problems such as necrosis of surrounding tissues due to polymerization heat generated during the curing reaction, lack of direct connection with new bone, and adjacent vertebral fractures. Research and development of calcium phosphate cement is underway as a new bone cement to replace it.
現在までに数々のリン酸カルシウムセメントが開発されてきた。そのほとんどはリン酸四カルシウムやリン酸水素カルシウムなどを主材とし、酸-塩基反応により硬化する。しかし、酸-塩基反応による炎症反応の恐れや硬化時間が長いことが問題点として挙げられている。 To date, a number of calcium phosphate cements have been developed. Most of them use tetracalcium phosphate or calcium hydrogen phosphate as the main material and harden by acid-base reaction. However, there are problems of fear of inflammatory reaction due to acid-base reaction and long curing time.
本願発明者らは、先にイノシトールリン酸のキレート能を応用したキレート硬化型アパタイトセメントの開発に成功している (特許文献１)。このセメントはイノシトールリン酸のキレート能により硬化するため、上記の問題の恐れがない。また、混練液へのデキストラン硫酸ナトリウムやアルギン酸ナトリウムのような多糖類添加による高強度化にも成功し、臨床応用に向け大きく前進している(特許文献２)。さらに、イノシトールリン酸で処理したリン酸三カルシウムを用いた骨セメントも開発している（特許文献３）。さらにカルシウム塩粉末の粒度分布を最適化することにより圧縮強度を高めることにも成功している（特許文献４）。また、特許文献４には、適用する疾患に応じて、でんぷん、グリコサミノグリカン、アルギン酸、キチン、キトサン、ヘパリン等の多糖類も添加可能であることが記載されている。しかしながら、特許文献４には、多糖類の添加については具体的に記載されておらず、添加の目的も「適用する疾患に応じて」と記載されているのみであり、キトサンを加えることによる効果やキトサンと他の多糖類との相違については記載も示唆もされていない。 The inventors of the present application have succeeded in the development of a chelate-hardening type apatite cement using the inositol phosphate chelating ability (Patent Document 1). Since this cement is hardened by the chelating ability of inositol phosphate, there is no fear of the above problems. In addition, it has succeeded in increasing the strength by adding polysaccharides such as sodium dextran sulfate and sodium alginate to the kneaded liquid, and has made great progress toward clinical application (Patent Document 2). Furthermore, a bone cement using tricalcium phosphate treated with inositol phosphate has also been developed (Patent Document 3). Furthermore, it has succeeded in raising compressive strength by optimizing the particle size distribution of calcium salt powder (patent document 4). Patent Document 4 describes that polysaccharides such as starch, glycosaminoglycan, alginic acid, chitin, chitosan, and heparin can be added depending on the disease to be applied. However, Patent Document 4 does not specifically describe the addition of polysaccharides, and the purpose of the addition is only described as “depending on the disease to be applied”, and the effect of adding chitosan There is no description or suggestion of the difference between chitosan and other polysaccharides.
従来より、PMMAは、注射器を用いて経皮的に患部に注入されている。骨充填に用いる組成物を注射器で注入できれば、低侵襲的に治療を行うことができるので、患者の負担が少なく好ましい。PMMAの欠点を解消した、リン酸カルシウム系の充填材に係る特許文献２にも、注射器による注入について言及されている。注射器により注入する場合には、針を通して注入が行われるので、針穴に詰まらない程度に低粘度の組成物を調製する必要がある。低粘度の組成物は、固形物に対する液体の比率を高めることにより調製可能である。特許文献２記載の組成物は、硬化後の強度が高く、生体適合性にも優れている。しかしながら、この組成物を、注射器による注入が可能な粘度になる程度に液体の比率を高くすると、硬化後の強度が満足できない。 Conventionally, PMMA has been percutaneously injected into the affected area using a syringe. If the composition used for bone filling can be injected with a syringe, treatment can be performed in a minimally invasive manner. Patent Document 2 relating to a calcium phosphate filler that eliminates the disadvantages of PMMA also mentions injection by a syringe. When injecting with a syringe, since injection is performed through a needle, it is necessary to prepare a composition having a low viscosity so as not to clog the needle hole. Low viscosity compositions can be prepared by increasing the liquid to solid ratio. The composition described in Patent Document 2 has high strength after curing and excellent biocompatibility. However, if the ratio of the liquid is increased to such a level that the composition can be injected with a syringe, the strength after curing cannot be satisfied.
従って、本発明の目的は、注射器等による患部への注入が可能であり、それでいて、硬化後の強度が十分に大きい、骨や歯等の充填に利用可能な組成物を提供することである。 Accordingly, an object of the present invention is to provide a composition that can be used for filling bones, teeth, and the like that can be injected into an affected area with a syringe or the like and yet has a sufficiently high strength after curing.
本願発明者らは、鋭意研究の結果、イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸三カルシウムと、キトサンとを併用することにより、注射器等で注入可能な粘度にまで液の比率を高めても、硬化物の強度を十分に大きくすることができることを見出し、本発明を完成した。 As a result of earnest research, the inventors of the present application have increased the ratio of the liquid to a viscosity that can be injected with a syringe or the like by using chitosan in combination with hydroxyapatite and / or tricalcium phosphate treated with inositol phosphate. In addition, the present inventors have found that the strength of the cured product can be sufficiently increased, thereby completing the present invention.
すなわち、本発明は、イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸カルシウムと、キトサンと、水とを含む、注入が可能なペースト状組成物を提供する。本発明は、また、上記本発明の組成物から成る骨又は歯充填材を提供する。 That is, the present invention provides an injectable paste-like composition comprising inositol phosphate-treated hydroxyapatite and / or calcium phosphate, chitosan, and water. The present invention also provides a bone or tooth filler comprising the composition of the present invention.
本発明により、注射器等による患部への注入が可能であり、それでいて、硬化後の強度が十分に大きい、イノシトールリン酸処理したヒドロキシアパタイト又はリン酸三カルシウム、そしてキトサンを含有する、骨や歯等の充填に利用可能な組成物が初めて提供された。本発明の組成物を用いれば、PMMAの上記欠点を解消し、さらに、経皮的な患部への組成物の注入を注射器により低侵襲的に行うことができるので、患者の負担が少なく非常に有利である。また、硬化時間も公知のものよりも短い。従って、本発明は、経皮的椎体形成術のような骨や歯等の治療に大いに貢献するものと考えられる。 According to the present invention, injection into the affected area by a syringe or the like is possible, and yet the strength after curing is sufficiently high, including inositol phosphate-treated hydroxyapatite or tricalcium phosphate, and chitosan, bones, teeth, etc. For the first time, a composition that can be used to fill the container was provided. By using the composition of the present invention, the above-mentioned drawbacks of PMMA can be eliminated, and furthermore, the composition can be injected into the affected area percutaneously with a syringe in a minimally invasive manner. It is advantageous. Also, the curing time is shorter than known ones. Therefore, it is considered that the present invention greatly contributes to the treatment of bones and teeth such as percutaneous vertebroplasty.
上記の通り、本発明の組成物は、イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸三カルシウムと、キトサンと、水とを含む。 As described above, the composition of the present invention includes inositol phosphate-treated hydroxyapatite and / or tricalcium phosphate, chitosan, and water.
ヒドロキシアパタイト及び／又はリン酸三カルシウムをイノシトールリン酸で処理することは、特許文献２及び特許文献３に記載されており、本発明においてもこれらの文献に記載された公知の方法によりイノシトールリン酸処理を行うことができる。簡単に述べると、イノシトールリン酸としては、イノシトール６リン酸（すなわちフィチン酸）が好ましい。また、ここで、「イノシトールリン酸処理」は、イノシトールリン酸の塩による処理をも包含し、塩としては、ナトリウム塩やカリウム塩のようなアルカリ金属塩が好ましい。イノシトールリン酸（塩の形であってもよい。本明細書及び特許請求の範囲において同様）処理は、イノシトールリン酸の水溶液とヒドロキシアパタイト及び／又はリン酸カルシウム粉末を混合することにより行うことができる。この場合、イノシトールリン酸水溶液の濃度は特に限定されないが、通常、1000ppm〜10000ppm程度、好ましくは1000〜5000ppm程度、さらに好ましくは1000〜3000ppm程度である。また、イノシトールリン酸水溶液のpHは、中性域（６〜８程度）が好ましく、また、処理は常温で行うことができる。混合後の水溶液を凍結乾燥処理することにより、表面にイノシトールリン酸が吸着したヒドロキシアパタイト及び／又はリン酸三カルシウム粉末が得られる。 Treatment of hydroxyapatite and / or tricalcium phosphate with inositol phosphate is described in Patent Document 2 and Patent Document 3, and also in the present invention, inositol phosphate is obtained by a known method described in these documents. Processing can be performed. Briefly, inositol phosphate is preferably inositol 6-phosphate (that is, phytic acid). Here, “inositol phosphate treatment” includes treatment with a salt of inositol phosphate, and the salt is preferably an alkali metal salt such as sodium salt or potassium salt. Inositol phosphate treatment (which may be in the form of a salt, as in the present specification and claims) can be performed by mixing an aqueous solution of inositol phosphate with hydroxyapatite and / or calcium phosphate powder. In this case, the concentration of the inositol phosphate aqueous solution is not particularly limited, but is usually about 1000 ppm to 10000 ppm, preferably about 1000 to 5000 ppm, and more preferably about 1000 to 3000 ppm. In addition, the pH of the inositol phosphate aqueous solution is preferably in the neutral range (about 6 to 8), and the treatment can be performed at room temperature. The aqueous solution after mixing is freeze-dried to obtain hydroxyapatite and / or tricalcium phosphate powder having inositol phosphate adsorbed on its surface.
ヒドロキシアパタイト（水酸アパタイトとも呼ばれる）は、骨セメントやクロマトグラフィー用担体等の種々の用途において用いられている周知の材料であり、その製造方法も周知である。ヒドロキシアパタイトは、水酸化カルシウム懸濁液にリン酸水溶液を滴下することによる湿式合成法により製造することができる（詳細は下記実施例に記載）。また、市販のヒドロキシアパタイト粉末をさらにボールミル等で粉砕した粉末（機械粉砕ヒドロキシアパタイト）も用いることができる。低粘度の組成物で強度の大きな硬化物を得る観点から、湿式合成法により製造したヒドロキシアパタイトが好ましい。 Hydroxyapatite (also called hydroxyapatite) is a well-known material used in various applications such as bone cement and chromatographic carrier, and its production method is also well known. Hydroxyapatite can be produced by a wet synthesis method by dropping a phosphoric acid aqueous solution into a calcium hydroxide suspension (details are described in the following examples). Further, a powder obtained by further pulverizing commercially available hydroxyapatite powder with a ball mill or the like (mechanically pulverized hydroxyapatite) can also be used. From the viewpoint of obtaining a cured product having high strength with a low viscosity composition, hydroxyapatite produced by a wet synthesis method is preferred.
リン酸三カルシウムとしては、α−リン酸三カルシウム(α−Ca3(PO4)2)及びβ−リン酸三カルシウム(β−Ca3(PO4)2) が好ましく、とりわけ、生体吸収性（最終的に自家骨に置き換わる性質）の観点からβ−リン酸三カルシウムが好ましい。 As the tricalcium phosphate, α-tricalcium phosphate (α-Ca 3 (PO 4 ) 2 ) and β-tricalcium phosphate (β-Ca 3 (PO 4 ) 2 ) are preferable. Β-tricalcium phosphate is preferable from the viewpoint of (the property of finally replacing autologous bone).
本発明の組成物は、さらにキトサンを含む。キトサンとしてはその塩も使用することができ、その塩としては、ナトリウム塩やカリウム塩のようなアルカリ金属塩が好ましい。キトサンの分子量は、特に限定されないが、通常数十万〜数百万程度である。また、キトサンは、完全に脱アセチル化されている必要はなく、通常の市販品にみられるように、脱アセチル化度は、約７０％以上、好ましく約８０〜８５％以上あればよい。組成物中のキトサン及び／又はその塩の含有量は、通常、2.5〜10質量％程度、好ましくは、５〜１０質量％程度である。キトサンは、塩酸塩等の酸付加塩の形態にあってもよい。上記の通り、本発明の組成物は、必須成分として水も含むが、キトサンの水溶液が市販されている（例えば、大日精化工業社製のダイキトサンW-10やダイキトサンコートGL等）ので、市販のキトサン水溶液と、前記イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸三カルシウムとを混合し、混練することにより本発明の組成物を簡便に得ることができ、好ましい。また、キトサンは粉末状のものを前記イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸三カルシウムと水と混練することによっても本発明の組成物を得ることができる。この場合、粉末状のキトサンとして、上記キトサン水溶液の凍結乾燥物を用いると水に溶解しやすく好ましい。 The composition of the present invention further comprises chitosan. As the chitosan, a salt thereof can also be used, and the salt is preferably an alkali metal salt such as sodium salt or potassium salt. The molecular weight of chitosan is not particularly limited, but is usually about several hundred thousand to several million. Chitosan does not have to be completely deacetylated, and the degree of deacetylation is about 70% or more, preferably about 80 to 85% or more as seen in ordinary commercial products. The content of chitosan and / or a salt thereof in the composition is usually about 2.5 to 10% by mass, preferably about 5 to 10% by mass. Chitosan may be in the form of an acid addition salt such as hydrochloride. As described above, the composition of the present invention also contains water as an essential component, but an aqueous solution of chitosan is commercially available (for example, Daikito San W-10 or Daichito Sun Coat GL manufactured by Dainichi Seika Kogyo Co., Ltd.). The composition of the present invention can be easily obtained by mixing and kneading a commercially available chitosan aqueous solution with the above-mentioned inositol phosphate-treated hydroxyapatite and / or tricalcium phosphate, which is preferable. The composition of the present invention can also be obtained by kneading chitosan with powdered hydroxyapatite and / or tricalcium phosphate treated with inositol phosphate. In this case, it is preferable to use a lyophilized product of the above chitosan aqueous solution as the powdery chitosan because it is easily dissolved in water.
本発明の組成物は、注射器等による注入が可能なものである。注射器に用いられる注射針の内径は、通常、0.4〜1.8mm程度であるので、この程度の通常の注射針を用いて注入可能である。この性質を達成することができる固液比は、キトサン水溶液を用いた場合には、1/0.80〜1/1.10程度、好ましくは1/0.85〜1/1.05程度、キトサン粉末を用いた場合には、1/0.50〜1/1.840.84程度である。ここで、「固液比」は、キトサン水溶液を混練する場合には、イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸カルシウムの質量（単位ｇ）と、キトサン水溶液の容量（単位ｍＬ）との比率として定義され、キトサン粉末を混練する場合には、イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸カルシウムの質量（単位ｇ）と、水の容量（単位ｍＬ）との比率として定義される。上記した市販のキトサン水溶液に、上記範囲の固液比が達成される量の前記イノシトールリン酸処理したヒドロキシアパタイト及び／又はリン酸三カルシウムとを混合し、混練することにより注射器等による注入が可能なペースト状の本発明の組成物を簡便に得ることができ、好ましい。 The composition of the present invention can be injected by a syringe or the like. Since the inner diameter of the injection needle used for the syringe is usually about 0.4 to 1.8 mm, the injection can be performed using the normal injection needle of this degree. The solid-liquid ratio that can achieve this property is about 1 / 0.80 to 1 / 1.10, preferably about 1 / 0.85 to 1 / 1.05 when a chitosan aqueous solution is used, and when chitosan powder is used. 1 / 0.50 to 1 / 1.840.84. Here, the “solid-liquid ratio” is the ratio between the mass (unit: g) of hydroxyapatite and / or calcium phosphate treated with inositol phosphate and the volume (unit: mL) of the chitosan aqueous solution when the chitosan aqueous solution is kneaded. In the case of kneading chitosan powder, the ratio is defined as the ratio between the mass (unit: g) of hydroxyapatite and / or calcium phosphate treated with inositol phosphate and the volume of water (unit: mL). The above commercially available chitosan aqueous solution is mixed with the above-mentioned inositol phosphate-treated hydroxyapatite and / or tricalcium phosphate in an amount that achieves the solid-liquid ratio in the above range, and can be injected by a syringe or the like by kneading. A paste-like composition of the present invention can be obtained easily and is preferred.
本発明の組成物は、骨や歯の充填材として用いることができる。本発明の組成物は、本発明の有利な特徴を利用して、注射器により患部に経皮的に注入することができる。注入された組成物は、公知の骨充填材と同様、患部において硬化する。本発明の組成物によれば、注射器による経皮的な注入が可能であるので、低侵襲的な治療が可能であり、患者の負担が少なく、また、注射針を利用できるので、従来よりも精密な治療が可能になる。 The composition of the present invention can be used as a filler for bones and teeth. The composition of the present invention can be percutaneously injected into an affected area by a syringe using the advantageous features of the present invention. The injected composition hardens in the affected area, similar to known bone fillers. According to the composition of the present invention, since transcutaneous injection by a syringe is possible, minimally invasive treatment is possible, the burden on the patient is small, and an injection needle can be used. Precise treatment is possible.
以下、本発明を実施例に基づきより具体的に説明する。もっとも、本発明は下記実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.
実施例１
1. HAp粉末の調製
1-1湿式合成HAp粉末の調製
0.5 M水酸化カルシウム懸濁液500 cm3を調製し、それに0.3 Mリン酸水溶液500 cm3を滴下した (滴下速度17 ml/min)。水酸化カルシウムとリン酸の濃度はCa/P=1.67 (モル比)となるように調整した。また、反応槽中のpHが10 < pH < 11となるようにpH調整剤 (25 % NH4OH)で調整した。リン酸水溶液滴下が終了した後、さらに1時間撹拌してから37℃に設定したインキュベータ内に24時間静置し、熟成させた。熟成後、吸引濾過にてHApスラリーを回収し、-80℃のフリーザーで一晩凍結させた。凍結させたHApスラリーは凍結乾燥機(LABCONCO製Free Zone)を用いて48時間乾燥し、湿式合成HApとした。
Example 1
1. Preparation of HAp powder
1-1 Preparation of wet synthetic HAp powder
A 0.5 M calcium hydroxide suspension (500 cm 3) was prepared, and a 0.3 M phosphoric acid aqueous solution (500 cm 3) was dropped into the suspension (dropping rate: 17 ml / min). The concentrations of calcium hydroxide and phosphoric acid were adjusted to be Ca / P = 1.67 (molar ratio). In addition, the pH in the reaction vessel was adjusted with a pH adjuster (25% NH 4 OH) so that 10 <pH <11. After completion of the dropwise addition of the phosphoric acid aqueous solution, the mixture was further stirred for 1 hour, and then left to stand in an incubator set at 37 ° C. for 24 hours for aging. After aging, the HAp slurry was collected by suction filtration and frozen overnight in a -80 ° C freezer. The frozen HAp slurry was dried for 48 hours using a freeze dryer (Free Zone manufactured by LABCONCO) to obtain wet synthetic HAp.
得られたHApを遊星型ボールミル (FRITSCH製 P-6型)を用いて下記の条件で粉砕した。ジルコニア製ポットに、HAp10.0 g とφ10 mm ジルコニアボール50個、精製水40 mLを入れ、回転数300 rpmで5分間湿式粉砕した。粉砕後、精製水を用いて容器から洗い流すように試料を回収し、吸引濾過にて粉砕HApを回収、乾燥して粉末を得た。 The obtained HAp was pulverized under the following conditions using a planetary ball mill (FRITSCH P-6 type). In a zirconia pot, 10.0 g of HAp, 50 φ10 mm zirconia balls, and 40 mL of purified water were placed, and wet pulverized for 5 minutes at a rotation speed of 300 rpm. After pulverization, a sample was collected so as to be washed out of the container with purified water, and pulverized HAp was collected by suction filtration and dried to obtain a powder.
1-2 機械粉砕HAp粉末の調製
HAp-100粉末(太平化学社製)10 g及びφ10 mmのジルコニアボール50 個、精製水40 mLを遊星型ボールミル（FRITSCH社製 P-6型）内に入れ、回転数300 rpmで5分間湿式粉砕した。粉砕後、精製水を用いて容器から洗い流すように試料を回収し、吸引濾過、乾燥して機械粉砕HAp粉末を回収した。
1-2 Preparation of machine-pulverized HAp powder
HAp-100 powder (made by Taihei Chemical Co., Ltd.) 10 g and 50 φ10 mm zirconia balls and 40 mL of purified water are placed in a planetary ball mill (PIT type FRITSCH) and wet for 5 minutes at 300 rpm. Crushed. After pulverization, a sample was collected so as to be washed out of the container with purified water, suction filtered, and dried to collect mechanically pulverized HAp powder.
2. フィチン酸(IP6)処理HAp粉末の調製
2-1湿式合成IP6-HAp粉末の調製
50質量%IP6水溶液 (和光純薬工業(株)製)を1.00 g 精秤し、精製水で300 cm3程度に希釈した後、水酸化ナトリウム水溶液を用いてpHを7.3に調整し、メスフラスコを用いて500 cm3にメスアップすることで濃度1000 ppmのIP6水溶液を調製した。
2. Preparation of phytic acid (IP6) treated HAp powder
2-1 Preparation of wet synthetic IP6-HAp powder
1.00 g of 50% IP6 aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.) is accurately weighed, diluted to about 300 cm 3 with purified water, adjusted to pH 7.3 with aqueous sodium hydroxide solution, and a volumetric flask. An IP6 aqueous solution with a concentration of 1000 ppm was prepared by measuring the volume up to 500 cm 3 using a solution.
濃度1000 ppmのIP6水溶液200 cm3に、湿式合成HAp粉末10 gを懸濁し、37℃、撹拌速度400 rpmで5時間撹拌した。これを吸引濾過し、得られた濾過物を精製水で洗浄した後、-80 ℃で一晩凍結させた。凍結させたIP6-HApは凍結乾燥機 (LABCONCO製Free Zone)を用いて24時間乾燥し、「湿式合成IP6-HAp粉末」を得た。 10 g of wet synthetic HAp powder was suspended in 200 cm 3 of an IP6 aqueous solution having a concentration of 1000 ppm and stirred at 37 ° C. and a stirring speed of 400 rpm for 5 hours. This was subjected to suction filtration, and the obtained filtrate was washed with purified water and then frozen at −80 ° C. overnight. The frozen IP6-HAp was dried for 24 hours using a freeze dryer (Free Zone manufactured by LABCONCO) to obtain “wet synthetic IP6-HAp powder”.
2-2機械粉砕IP6-HAp粉末の調製
濃度1000 ppmのIP6水溶液400 cm3に、機械粉砕HAp粉末10 gを懸濁し、37 ℃、撹拌速度400 rpmで5時間撹拌した。これを吸引濾過し、得られた濾過物を精製水で洗浄した後、-80 ℃で一晩凍結させた。凍結させたIP6-HApは凍結乾燥機(LABCONCO製Free Zone)を用いて24時間乾燥し、「機械粉砕IP6-HAp粉末」を得た。
2-2 Preparation of mechanically pulverized IP6-HAp powder 10 g of mechanically pulverized HAp powder was suspended in 400 cm 3 of an IP6 aqueous solution having a concentration of 1000 ppm and stirred at 37 ° C. and a stirring speed of 400 rpm for 5 hours. This was subjected to suction filtration, and the obtained filtrate was washed with purified water and then frozen at −80 ° C. overnight. The frozen IP6-HAp was dried for 24 hours using a freeze dryer (Free Zone manufactured by LABCONCO) to obtain “mechanically pulverized IP6-HAp powder”.
3. ペースト状組成物の作製
前記湿式合成IP6-HAp粉末及び機械粉砕IP6-HAp粉末に対してダイキトサンW-10 (大日精化工業社製10%キトサン水溶液)をそれぞれ0.35〜1.10 mL (固液比で1/0.35〜1/1.10)となるように加えてゴムヘラを用いて混練してペースト状組成物を作製した。
3. Preparation of paste-like composition Daichitosan W-10 (10% chitosan aqueous solution manufactured by Dainichi Seika Kogyo Co., Ltd.) was added to the wet synthetic IP6-HAp powder and mechanically pulverized IP6-HAp powder, respectively. A paste-like composition was prepared by kneading with a rubber spatula so that the liquid ratio was 1 / 0.35 to 1 / 1.10).
試料片は前記ペースト状組成物をφ5 mm塩化ビニル成形器内に注入し、取り出して円柱状に成形することにより作製した。成形した試料片は37 ℃、湿度100%に調節した恒温機ヒータ式インキュベータ(三洋電機社製)に24時間静置して硬化させた。試料片のサイズはφ4.5〜5 mm、高さ6〜8 mmであった。 A sample piece was prepared by injecting the paste composition into a φ5 mm vinyl chloride molding machine, taking it out and molding it into a cylindrical shape. The molded specimen was allowed to stand for 24 hours in a constant temperature heater incubator (manufactured by Sanyo Electric Co., Ltd.) adjusted to 37 ° C. and 100% humidity to be cured. The size of the sample piece was φ4.5 to 5 mm and the height was 6 to 8 mm.
4. 硬化物の力学特性評価
得られた硬化物の力学特性はすべて圧縮強度試験で評価した。試験機はSHIMADZU製のAUTOGRAPH AGS-Jを用いた。測定はクロスヘッドスピード0.5 mm・ min -1、設定荷重5 kNの条件で行った。
4. Evaluation of mechanical properties of cured products All mechanical properties of the obtained cured products were evaluated by compressive strength tests. The tester used was AUTOGRAPH AGS-J made by SHIMADZU. The measurement was performed under the conditions of a crosshead speed of 0.5 mm · min −1 and a set load of 5 kN.
図1に作製した硬化物試料片の圧縮強度を示す。湿式合成IP6-HAp粉末の場合には、固液比1/1.05の調製条件にて最大強度36 MPaを示した。機械粉砕IP6-HAp粉末の場合には、固液比1/0.45の調製条件にて最大強度36 MPaを示した。 FIG. 1 shows the compressive strength of the cured sample piece. In the case of the wet synthetic IP6-HAp powder, the maximum strength of 36 MPa was exhibited under the preparation conditions with a solid-liquid ratio of 1 / 1.05. In the case of mechanically pulverized IP6-HAp powder, a maximum strength of 36 MPa was exhibited under the preparation conditions with a solid-liquid ratio of 1 / 0.45.
実施例２
実施例１で用いたダイキトサンW-10に代えてダイキトサンコートGL(大日精化工業社製キトサン)の５及び１０質量%水溶液それぞれと、濃度1000 ppmのIP6水溶液に代えて濃度5000 ppm IP6水溶液を用い、他は実施例１と同様にしてペースト状組成物を調製した。
Example 2
Instead of Daichitosan W-10 used in Example 1, Daichitosan Coat GL (chitosan manufactured by Dainichi Seika Kogyo Co., Ltd.) 5 and 10% by mass aqueous solution, respectively, and a concentration of 5000 ppm IP6 instead of 1000 ppm IP6 aqueous solution A paste-like composition was prepared in the same manner as in Example 1 except that the aqueous solution was used.
図2に作製した硬化物試料片の圧縮強度を示す。湿式合成IP6-HAp粉末の場合には、濃度10質量%のダイキトサンコートGLを用いた場合、固液比1/1.05にて最大強度27 MPaを示した。また、5質量%の場合では固液比1/0.95にて最大強度16 MPaを示した。機械粉砕IP6-HAp粉末の場合には、固液比1/0.60の調製条件にて最大強度11 MPaを示した。 FIG. 2 shows the compressive strength of the cured sample piece produced. In the case of the wet synthetic IP6-HAp powder, the maximum strength of 27 MPa was exhibited at a solid-liquid ratio of 1 / 1.05 when a 10% by mass concentration of Daikito Suncoat GL was used. In the case of 5% by mass, the maximum strength was 16 MPa at a solid-liquid ratio of 1 / 0.95. In the case of mechanically pulverized IP6-HAp powder, a maximum strength of 11 MPa was exhibited under the preparation conditions with a solid-liquid ratio of 1 / 0.60.
実施例３、比較例１〜４
β-TCP粉末は市販β-TCP-100(太平化学社製)10 gを遊星型ボールミルにより湿式粉砕して調製した。まず、10 mmφのジルコニアボールで4 h 粉砕(β-TCP-4h)した。それを3000 ppmに調整したイノシトールリン酸(IP6)水溶液で24時間表面修飾し、24時間の凍結乾燥を経て「表面修飾粉末(IP6/β-TCP-4h)」を得た。組成物作製にはIP6/β-TCP 粉末と次に示す混練液を種々の固液比、1/0.45、1/0.50、1/0.55で混練し、成形器に充填して試料片(直径: 6 mm, 高さ: 12 mm)を作製した。混練液としては、(i) 純水(Water、比較例１）、(ii) アルギン酸ナトリウム(Alg、比較例２)、(iii) デキストラン硫酸ナトリウム(Dex、比較例３)、(iv) コンドロイチン硫酸ナトリウム(Chond、比較例４)及び(v) ダイキトサンW-10(Chito、実施例３)の水溶液をそれぞれ使用した。作製したペースト状組成物はヒトの体内環境下に近い37℃, 相対湿度100% のインキュベーター(三洋電機社製)中で24 時間硬化させ、SHIMADZU製の万能試験機を用いて圧縮強度を測定した。その結果を図３に示す。これらの結果から、本発明の組成物を用いた場合、従来技術に比し格別に優れた圧縮強度を有していることが分かる。
Example 3 and Comparative Examples 1-4
β-TCP powder was prepared by wet pulverizing 10 g of commercially available β-TCP-100 (manufactured by Taihei Chemical Co., Ltd.) with a planetary ball mill. First, it was pulverized with 10 mmφ zirconia balls for 4 h (β-TCP-4h). It was surface modified with an inositol phosphate (IP6) aqueous solution adjusted to 3000 ppm for 24 hours, and lyophilized for 24 hours to obtain “surface modified powder (IP6 / β-TCP-4h)”. For composition preparation, IP6 / β-TCP powder and the following kneading liquid were kneaded at various solid-liquid ratios, 1 / 0.45, 1 / 0.50, 1 / 0.55, filled into a molding machine, and sample pieces (diameter: 6 mm, height: 12 mm). As the kneading liquid, (i) pure water (Water, Comparative Example 1), (ii) sodium alginate (Alg, Comparative Example 2), (iii) dextran sodium sulfate (Dex, Comparative Example 3), (iv) chondroitin sulfate Sodium (Chond, Comparative Example 4) and (v) aqueous solutions of Daichitosan W-10 (Chito, Example 3) were used. The prepared paste-like composition was cured for 24 hours in an incubator (manufactured by Sanyo Electric Co., Ltd.) at 37 ° C and 100% relative humidity close to the human body environment, and the compressive strength was measured using a universal testing machine manufactured by SHIMADZU. . The result is shown in FIG. From these results, it can be seen that when the composition of the present invention is used, it has exceptionally superior compressive strength as compared with the prior art.
また、硬化物の結晶相を同定するためにX線回折装置(リガク社製XRD)を用いて結晶相を同定した。その結果、混練液の成分に関係なく、原料粉末のβ-TCPの結晶構造を維持したまま硬化していることが確認された。 Further, in order to identify the crystal phase of the cured product, the crystal phase was identified using an X-ray diffractometer (XRD manufactured by Rigaku Corporation). As a result, it was confirmed that the material powder was cured while maintaining the crystal structure of β-TCP regardless of the components of the kneaded liquid.
続いて、日本工業規格(JIS T 6602)に準拠して、ペースト状組成物の稠度及び硬化時間を測定した。その結果、本発明のペースト状組成物の稠度は、既に臨床応用されているBiopex-R(HOYA社の商品名)と同程度な稠度を有していることが分かった。そのため、適度な稠度で注射器からの注入可能かつ、患部からの漏出を防止できることが期待される。次に、ペースト状組成物の硬化時間を測定した。特許文献２で用いたコンドロイチン硫酸ナトリウム(Chond)の初期硬化時間は、約42分であった(β-TCP単一相)。一方、本発明に従い、ダイキトサンW-10(Chito)を混練液に使用することで、ペースト状組成物の初期硬化時間は、最短で約8分間まで短縮することに成功した。以上の結果、ダイキトサンW-10(Chito)を混練液に使用することで、硬化物の圧縮強度の向上ならびに、硬化時間の短縮に成功した。 Subsequently, according to Japanese Industrial Standard (JIS T 6602), the consistency and curing time of the paste-like composition were measured. As a result, it was found that the consistency of the paste-like composition of the present invention was comparable to that of Biopex-R (trade name of HOYA) already applied clinically. Therefore, it is expected that injection from a syringe can be performed with an appropriate consistency and leakage from the affected area can be prevented. Next, the curing time of the paste-like composition was measured. The initial curing time of sodium chondroitin sulfate (Chond) used in Patent Document 2 was about 42 minutes (β-TCP single phase). On the other hand, by using Daichitosan W-10 (Chito) in the kneading liquid according to the present invention, the initial curing time of the paste-like composition was successfully shortened to about 8 minutes at the shortest. As a result, by using Daichitosan W-10 (Chito) in the kneading liquid, the compression strength of the cured product was improved and the curing time was shortened.
実施例４及び実施例５
１. α-リン酸三カルシウム(α-TCP)粉末の調製
α-TCPは次のようにして調製した。α-TCP-A粉末(太平化学社製)10g及びφ10mmのジルコニアボール50個、精製水40mLを遊星型ボールミル（FRITSCH社製 P-6型）内に入れ、回転数300rpmで120分間湿式粉砕した。粉砕後、吸引ろ過し、固形物を凍結乾燥することで粉末を得た。
Example 4 and Example 5
1. Preparation of α-tricalcium phosphate (α-TCP) powder α-TCP was prepared as follows. 10g of α-TCP-A powder (Taihei Chemical Co., Ltd.) and 50 zirconia balls of φ10mm and 40mL of purified water were placed in a planetary ball mill (FRITSCH P-6 type) and wet-ground for 120 minutes at a rotation speed of 300rpm. . After pulverization, suction filtration was performed, and the solid was freeze-dried to obtain a powder.
２. イノシトールリン酸(IP6)処理α-TCP粉末の調製
得られたα-TCP粉末を、濃度1000ppmのIP6水溶液で24時間かき混ぜて表面修飾後、吸引ろ過し、固形物を凍結乾燥して「IP6-α-TCP粉末」を調製した。
2. Preparation of inositol phosphate (IP6) -treated α-TCP powder The obtained α-TCP powder was agitated for 24 hours with an IP6 aqueous solution with a concentration of 1000 ppm, subjected to surface filtration, suction filtered, and the solid was freeze-dried. IP6-α-TCP powder ”was prepared.
３. HAp粉末の調製
HAp-100粉末(太平化学社製)10 g及びφ10 mmのジルコニアボール50個、精製水40 mLを遊星型ボールミル（FRITSCH社製 P-6型）内に入れ、回転数300 rpmで5分間湿式粉砕した。粉砕後、精製水を用いて容器から洗い流すように試料を回収し、吸引濾過、乾燥して機械粉砕HAp粉末を回収した。
3. Preparation of HAp powder
HAp-100 powder (made by Taihei Chemical Co., Ltd.) 10 g and 50 φ10 mm zirconia balls and 40 mL of purified water are placed in a planetary ball mill (FR-6 P-6) and wet for 5 minutes at a rotation speed of 300 rpm. Crushed. After pulverization, a sample was collected so as to be washed out of the container with purified water, suction filtered, and dried to collect mechanically pulverized HAp powder.
４. イノシトールリン酸(IP6)処理HAp粉末の調製
濃度1000 ppmのIP6水溶液400 cm3に、湿式合成HAp粉末10 gを懸濁し、撹拌速度400 rpmで5時間撹拌した。これを吸引濾過し、得られた濾過物を精製水で洗浄した後、-80 ℃で一晩凍結させた。凍結させたIP6-HApは凍結乾燥機 (LABCONCO製FreeZone)を用いて24時間乾燥し、「IP6-HAp粉末」を得た。
4. Preparation of Inositol Phosphate (IP6) -treated HAp Powder 10 g of wet synthetic HAp powder was suspended in 400 cm 3 of an IP6 aqueous solution having a concentration of 1000 ppm and stirred at a stirring speed of 400 rpm for 5 hours. This was subjected to suction filtration, and the obtained filtrate was washed with purified water and then frozen at −80 ° C. overnight. The frozen IP6-HAp was dried for 24 hours using a freeze dryer (Freezone manufactured by LABCONCO) to obtain “IP6-HAp powder”.
５. ダイキトサン粉末の調製
市販のダイキトサンコートGL(大日精化工業社製10%キトサン水溶液)および炭酸水素ナトリウムを用いてpH7に調整したダイキトサンコートGL、市販のダイキトサンW-10(大日精化工業社製10%キトサン水溶液)を凍結乾燥しダイキトサン粉末を得た。
5. Preparation of Daikitosan Powder Commercially available Daichitosan Coat GL (10% chitosan aqueous solution manufactured by Dainichi Seika Kogyo Co., Ltd.), Daikito Sun Coat GL adjusted to pH 7 with sodium hydrogen carbonate, Commercial Daikito San W-10 (large 10% chitosan aqueous solution (Nissei Kagaku Kogyo Co., Ltd.) was freeze-dried to obtain dichitosan powder.
６. α-TCPセメントの作製（実施例４）
上記２で得られたIP6-α-TCP粉末を0.5g、上記５で得られたダイキトサン粉末を0.02g秤量し、これに純水を0.28〜0.42mL加え、混練してセメントペーストを調製した。調製したセメントペーストをフッ素樹脂製の成形器（直径6ｍｍ、高さ12ｍｍ）に手作業で充填後、押し出して試験片を作製し、これを室温で24時間静置硬化させた。作製した組成物の組成及び固液比を下記表１に示す。
6. Production of α-TCP cement (Example 4)
0.5 g of the IP6-α-TCP powder obtained in 2 above and 0.02 g of the dichitosan powder obtained in 5 above were weighed, 0.28 to 0.42 mL of pure water was added thereto, and kneaded to prepare a cement paste. . The prepared cement paste was manually filled into a fluororesin molding machine (diameter 6 mm, height 12 mm) and then extruded to produce a test piece, which was allowed to stand and cure at room temperature for 24 hours. The composition and solid-liquid ratio of the prepared composition are shown in Table 1 below.
７. HApセメントの作製（実施例５）
上記４で得られたIP6-HAp粉末を1.0g、純水を0.5mL秤量し、これに上記５で得られたダイキトサンGL粉末を0.06〜0.20g加え、混練してセメントペーストを調製した。調製したセメントペーストをフッ素樹脂製の成形器（直径6ｍｍ、高さ12ｍｍ）に手作業で充填後、押し出して試験片を作製し、これを室温で24時間静置硬化させた。作製した組成物の組成及び固液比等を下記表２に示す。
7. Production of HAp cement (Example 5)
1.0 g of the IP6-HAp powder obtained in the above 4 and 0.5 mL of pure water were weighed, 0.06 to 0.20 g of the dichitosan GL powder obtained in the above 5 was added thereto, and kneaded to prepare a cement paste. The prepared cement paste was manually filled into a fluororesin molding machine (diameter 6 mm, height 12 mm) and then extruded to produce a test piece, which was allowed to stand and cure at room temperature for 24 hours. The composition and solid-liquid ratio of the produced composition are shown in Table 2 below.
得られた硬化物の圧縮強度及び相対密度をそれぞれ図４（実施例４）及び図５（実施例５）に示す。なお、ここで、相対密度は、HAp（3.16g/cm3）およびα-TCP（2.86g/cm3）の理論密度を基準とした場合の相対比率（％）を意味する。また、実施例４及び５で調製した組成物（硬化前のもの）は、注射器で注入可能であった。 The compression strength and relative density of the obtained cured product are shown in FIG. 4 (Example 4) and FIG. 5 (Example 5), respectively. Here, the relative density means a relative ratio (%) based on the theoretical density of HAp (3.16 g / cm 3 ) and α-TCP (2.86 g / cm 3 ). Moreover, the composition (the thing before hardening) prepared in Example 4 and 5 was injectable with the syringe.
本発明は、骨や歯の充填に利用可能である。 The present invention can be used for filling bones and teeth.
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| CN104524627A (en) * | 2014-12-23 | 2015-04-22 | 南京航空航天大学 | Method for preparing high-strength novel hydroxyapatite bone cement |
| WO2023053710A1 (en) * | 2021-09-30 | 2023-04-06 | 富士フイルム株式会社 | Tissue restorative material kit and tissue restoration method |
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| JPH03261643A (en) * | 1990-03-09 | 1991-11-21 | Sumitomo Chem Co Ltd | Curable composition |
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| JPH07112023A (en) * | 1993-10-20 | 1995-05-02 | Matsumoto Shika Univ | Osteogenesis material |
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| JP2005095346A (en) * | 2003-09-25 | 2005-04-14 | Meiji Univ | Material for cement, and cement |
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| JPH01152104A (en) * | 1987-12-08 | 1989-06-14 | Hokkaido Soda Kk | Preparation of water-soluble chitosan salt powder |
| JPH0277261A (en) * | 1987-12-28 | 1990-03-16 | Asahi Optical Co Ltd | Composite composition for producing cured body of calcium phosphate system and production of cured body |
| JPH02275812A (en) * | 1989-04-17 | 1990-11-09 | Asahi Optical Co Ltd | Liquid agent for hardened calcium phosphate and hardened material produced by using the agent |
| JPH03261643A (en) * | 1990-03-09 | 1991-11-21 | Sumitomo Chem Co Ltd | Curable composition |
| JPH0731673A (en) * | 1993-07-19 | 1995-02-03 | Asahi Optical Co Ltd | Bioabsorbable polymer-containing curable bone filling material |
| JPH07112023A (en) * | 1993-10-20 | 1995-05-02 | Matsumoto Shika Univ | Osteogenesis material |
| JPH11347112A (en) * | 1998-06-08 | 1999-12-21 | Matsumoto Dental College | Production of osteogenetic material |
| JP2001314497A (en) * | 2000-05-02 | 2001-11-13 | Univ Nihon | Composition of matter for biomaterial and hardened body thereof |
| JP2004024319A (en) * | 2002-06-21 | 2004-01-29 | Matsumoto Shika Univ | Granule bone prosthetic material and production method therefor |
| JP2006522641A (en) * | 2003-04-08 | 2006-10-05 | エイディーエイ ファウンデーション | Premixed self-hardening bone graft paste |
| JP2005095346A (en) * | 2003-09-25 | 2005-04-14 | Meiji Univ | Material for cement, and cement |
| WO2008090648A1 (en) * | 2007-01-25 | 2008-07-31 | Meiji University | Cement material and cement |
| JP2009178225A (en) * | 2008-01-29 | 2009-08-13 | Meiji Univ | Cement composition, cement kit, cement and method of manufacturing cement |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104524627A (en) * | 2014-12-23 | 2015-04-22 | 南京航空航天大学 | Method for preparing high-strength novel hydroxyapatite bone cement |
| WO2023053710A1 (en) * | 2021-09-30 | 2023-04-06 | 富士フイルム株式会社 | Tissue restorative material kit and tissue restoration method |
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|---|---|
| JP5936107B2 (en) | 2016-06-15 |
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