JPWO2014129382A1 - 多糖粉末およびこれを含む癒着防止材 - Google Patents
多糖粉末およびこれを含む癒着防止材 Download PDFInfo
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- JPWO2014129382A1 JPWO2014129382A1 JP2015501419A JP2015501419A JPWO2014129382A1 JP WO2014129382 A1 JPWO2014129382 A1 JP WO2014129382A1 JP 2015501419 A JP2015501419 A JP 2015501419A JP 2015501419 A JP2015501419 A JP 2015501419A JP WO2014129382 A1 JPWO2014129382 A1 JP WO2014129382A1
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- polysaccharide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
- C08L3/02—Starch; Degradation products thereof, e.g. dextrin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
Abstract
Description
本発明の多糖粉末は、全体積の30体積%以上の粒径(直径)が200〜750μmである粒度分布を有する。このような粒度分布を有する多糖粉末は、良好な水溶性を示す。ここで、200〜750μmである粒度分布を有する多糖粉末の含有量が全体積の30体積%未満である場合には、水溶性に劣り、急な手術現場に良好に対応できない。好ましくは、本発明の多糖粉末は、全体積の40体積%以上、より好ましくは50体積%以上、特に好ましくは60体積%以上の粒径が200〜750μmである粒度分布を有する。ここで、200〜750μmである粒度分布を有する多糖粉末の含有量の上限は、特に制限されないが、水溶性の向上などを考慮すると、70体積%以下であることが好ましく、65体積%以下であることがより好ましく、55体積%以下であることが特に好ましい。
本発明の多糖粉末の製造方法(粒度分布の調節方法)は、多糖粉末の粒度分布を粒径が200〜750μmである粉末の含有量を粉末の全体積の30体積%以上となるように調節することができる方法であれば特に制限されず、通常の分級によって調節されてもよい。好ましくは、上記のようにして調製された多糖を溶媒に溶解して多糖溶液を調製し(多糖溶液調製工程);前記多糖溶液を凍結乾燥して、凍結乾燥物を得(凍結乾燥工程);さらに前記凍結乾燥物を6000〜12000rpmの回転速度で粉砕する(粉砕工程)方法が好ましく適用される。すなわち、本発明は、多糖を溶媒に溶解して多糖溶液を調製し、前記多糖溶液を凍結乾燥して、凍結乾燥物を得、さらに前記凍結乾燥物を6000〜8000rpmの回転速度で粉砕することを有する、多糖乾燥粉末の製造方法をも提供する。このような方法によると、全体積の30体積%以上の粒径が200〜750μmである粒度分布を有する本発明の多糖粉末を効率的に製造できる。
本工程では、上記のようにして調製された多糖を溶媒に溶解して多糖溶液を調製する。
本工程では、上記で得られた多糖溶液を凍結乾燥して、凍結乾燥物を得る。
本工程では、上記で得られた凍結乾燥物を6000〜12000rpmの回転速度で粉砕する。これにより、上記で得られた凍結乾燥物は衝撃力により粉砕されて、本発明の粒度分布を有する多糖粉末が得られる。好ましくは、凍結乾燥物を6000〜8000rpmの回転速度で粉砕する。また、この際使用されうる粉砕機は、上記回転速度での粉砕が可能な機器であれば特に制限されない。例えば、超遠心粉砕機、カッターミル、ハンマーミル、フラッシュミル、ジェットミル、ボールミル、振動ボールミルなどが挙げられる。
上記多糖溶液調製工程、凍結乾燥工程及び粉砕工程によって、本発明の所望の粒度分布を有する多糖粉末が得られるが、必要であれば、上記粉末工程後、篩い工程(分級工程)を行ってもよい。当該工程を行うことにより、過度に大きな粉末を除去することができる。当該工程を行う場合の、篩の目開きは、特に制限されないが、過度に大きな粉末を除去するという観点からは、710〜1000μmであることが好ましい。また、当該篩い工程(分級工程)は、必要であれば、振動させながら行ってもよい。振動させながら篩いを行うことによって、粉末の回収量を増加させることができる。振動させながら篩いを行う際の振動条件は、特に制限されないが、例えば、1〜2mm/gの振幅で、20〜30℃で3〜10分間、振動させることが好ましい。
500mLフラスコ中、デキストリン(名糖産業株式会社製サンデックSD#100,Mw=15kDa)10gを、純水62.5gにダマや濁りがなくなるまで溶解した後、36wt%NaOH水溶液62.5gを添加して、室温(25℃)で90分間撹拌した。そこに、クロル酢酸10.31g(109.1mmol)に蒸留水を加え75gとしたクロル酢酸水溶液を添加し、60℃で6時間反応させた。室温(25℃)まで冷却した後、20%HCl水溶液を80mL添加し、CMデキストリンを含む反応液を得た。次に、エタノール4450mLおよび水180mLを含む5Lビーカー中に、撹拌下、上記で得た反応液全量を注ぎ込んだ。析出物を濾集し、最初に90%エタノール水溶液2Lで、次にエタノール2Lで洗浄した後、室温(25℃)で24時間減圧乾燥し、CMデキストリンを得た。このようにして得られたCMデキストリンのCM基量は0.8mmol/gであった。なお、CM基量は下記の方法に従って測定される。
多糖(CMデキストリン)0.2g(A(g))を秤取り、0.1mol/L水酸化ナトリウム水溶液20mLと80vol%メタノール水溶液10mLとの混合溶液に添加し、25℃で3時間撹拌した溶液に、1.0%フェノールフタレイン/90vol%エタノール水溶液を滴下し、0.05mol/L硫酸を使用して酸塩基逆滴定を行い、0.05mol/L硫酸の使用量(V1(mL))を測定する。酸型多糖を添加しないブランクでの0.05mol/L硫酸の使用量(V0(mL))を測定し、下記式(1)に従い、多糖のカルボキシ基量(Bmmol/g)を算出する。なお、使用した0.1mol/L水酸化ナトリウム水溶液、0.05mol/L硫酸の力価は、ともに1.00である。
1.溶液調製工程
20L容のステンレスタンクのジャケット部分に、冷却水(1.0℃に設定)を流した後、注射用蒸留水3250gを入れ、これに安定化剤としてのトレハロース300gを加えた。この溶液に、上記合成例1で得られたNHS化CMデキストリン300gを加え、5.0〜8.0℃で1時間程度攪拌し、NHS化CMデキストリンを上記溶液中に溶解した。溶解後、ポンプを用いてフィルター濾過を行ない、20L容のバックにろ液を回収した。
上記1.で回収された20L容のバックから凍結乾燥用トレイ(大きさ:44cm×29cm)に、ろ液を容量2.5Lとなるように分注した後、下記表1に示されるプログラムに従って、凍結乾燥して、多糖凍結乾燥体を得た。なお、下記乾燥工程は、1.7〜5.1Paの減圧条件下で行った。なお、下記予備凍結工程は、凍結乾燥装置(共和真空株式会社製 凍結乾燥装置 RL−201BS)を用いて、棚温度を5℃→−50℃まで165分かけて連続的に冷却し、−50℃で480分間凍結させた。次に、棚温度を−50℃から−10℃まで120分かけて徐々に上昇させ、−10℃で3600分間乾燥させた。次に、棚温度を−10℃から5℃まで480分かけて徐々に上昇させ、5℃で4200分間乾燥させた。次に、棚温度を5℃から30℃まで60分かけて徐々に上昇させ、30℃で600分間乾燥させた。
上記2.で得られた多糖凍結乾燥体を、へらで(3cm×3cm×3cm程度の大きさになるように)粗粉砕した後、超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を用いて、6000rpmで20分間粉砕し、多糖粉砕体を得た。この際、超遠心粉砕機にはスクリーンは使用しなかった。
このようにして得られた多糖粉砕物を電磁式篩い振とう機(株式会社 レッチェ製、商品名:電磁式ふるい振とう機 AS200)に設置し、篩い目開きが710μmの篩で、振幅1.2mm/gで、3分間分級し、710μmの篩いを通過したものを回収し、多糖分級体(多糖粉末(1))を得た。
粉末充填装置(粉末計量自動充填機 TM−F51Z3−L)を用いて、上記4.で篩いをかけた多糖分級体を、2.5±0.02gの精度で、バイアル(株式会社日本硝子産業株式会社、バイアル白30×50品)内に充填し、ゴム栓でバイアルを半打栓した。半打栓したバイアルを−700mmHg以上および−400mmHgの陰圧度となるように陰圧打栓した(バイアル(1))。
実施例1において、スクリーン径(直径)が10mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.〜4.の工程を繰り返して、多糖分級体(多糖粉末(2))を得た。
実施例1において、スクリーン径(直径)が8mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.〜4.の工程を繰り返して、多糖分級体(多糖粉末(3))を得た。
実施例1において、スクリーン径(直径)が6mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.〜4.の工程を繰り返して、多糖分級体(多糖粉末(4))を得た。
実施例1において、スクリーン径(直径)が2mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.〜4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(1))を得た。
1の5.の工程を繰り返して、比較バイアル(1)を得た。
実施例1において、スクリーン径(直径)が6mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.〜4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(2))を得た。
実施例1において、スクリーン径(直径)が8mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.〜4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(3))を得た。
実施例1において、スクリーン径(直径)が10mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.〜4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(4))を得た。
実施例1において、粉砕速度を12000rpmに変更した以外は、実施例1の1.〜4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(5))を得た。
実施例1において、溶液調製工程終了後に、ろ液を16mlバイアル(株式会社日本硝子産業株式会社、バイアル白30×50品)に充填した。得られたバイアルについて、実施例1 2.の凍結乾燥工程および5.の陰圧打栓工程を行い、比較例(6)(バルク体)を得た。
まず、多糖乾燥粉末(バイアル入り)の重量を測定する。次に、シリンジに溶解水として注射用蒸留水を吸い取り、JIGを用いて、一定の高さから溶解水(3.4〜3.6ml)を注入する。溶解水注入直後のバイアルの底部およびバイアル壁面の観察を行い、写真を撮影する。人の手で振盪を開始し、振盪(人の手でふる操作)を開始した時を0秒として30秒毎に溶解状態を観察する。また、観察と同時に写真を撮影する。この操作を合計時間が150秒となるまで続ける。ただし、途中で完全に溶解した場合は、溶解時間を記録し終了する。溶解水注入後のバイアル重量を測定し、溶解水注入量を算出する。
Claims (6)
- 全体積の30体積%以上の粒径が200〜750μmである粒度分布を有する、多糖を含む粉末。
- 累積体積比率が10%となる粒径(D10)が60〜120μmである、請求項1に記載の粉末。
- 累積体積比率が90%となる粒径(D90)が300〜520μmである、請求項1または2に記載の粉末。
- ピークトップが100〜500μmである、請求項1〜3のいずれか1項に記載の粉末。
- 前記多糖が3万〜12万の分子量を有する、請求項1〜4のいずれか1項に記載の粉末。
- 請求項1〜5のいずれか1項に記載の粉末を含む、癒着防止材。
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