JP2020172661A - 低エンドトキシンのキトサンの製造方法 - Google Patents
低エンドトキシンのキトサンの製造方法 Download PDFInfo
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- JP2020172661A JP2020172661A JP2020116148A JP2020116148A JP2020172661A JP 2020172661 A JP2020172661 A JP 2020172661A JP 2020116148 A JP2020116148 A JP 2020116148A JP 2020116148 A JP2020116148 A JP 2020116148A JP 2020172661 A JP2020172661 A JP 2020172661A
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- Prior art keywords
- chitosan
- acid
- endotoxin
- alkaline
- concentration
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- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
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- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
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- 229940050410 gluconate Drugs 0.000 description 1
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- OYHQOLUKZRVURQ-AVQMFFATSA-N linoelaidic acid Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-AVQMFFATSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
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- 239000012498 ultrapure water Substances 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
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- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
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- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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Abstract
Description
a)無菌環境において、殺菌済みの発熱因子が存在しない(pyrogen-free)設備および材料を使用する工程、
b)エンドトキシンを含有するキトサンを最大24時間で膨潤させる工程、
c)1kg/25Lから1.5kg/25Lのキトサンを、0.01Mから4.0Mの塩基性水酸化物(hydroxide base)中に溶解させる工程、
d)得られた塩基性のキトサン溶液を継続的に撹拌する工程、
e)該溶液を撹拌しながら、60℃から100℃で45分間から4時間加熱する工程、
f)該溶液を、その容積の最大10倍のエンドトキシンフリーの(endotoxin-free)超純水で濯ぐ工程、
g)該溶液をpH6.8から7.5の範囲で中和する工程、
h)超高純度の低エンドトキシンのキトサンスラリーを形成させ、スラリーをエンドトキシンフリーの閉鎖系(closed system)に移す工程、および
i)スラリーから余分な水分を取り除く工程を含む。
(a)水不溶性のキトサンを塩基性溶液と、第1の期間である1時間を超えて接触させる工程、
(b)望ましくはエンドトキシンフリー水を用いて、残存する塩基性溶液を取り除くために水不溶性のキトサンを濯ぐ工程、
(c)相間移動剤を含む反応溶液中で、水不溶性のキトサンを部分的にアセチル化する工程、
(d)界面活性剤を含み、約7.0から約7.4のpHを有する水性溶液に、部分的にアセチル化された水溶性のキトサンを溶解させる工程、
(e)該水性溶液に水混和性溶媒を加え、さらに水性溶液のpHを少なくとも8.0に調整して、水性溶液/水混和性溶媒の混合液から、低濃度のエンドトキシンを含む水溶性キトサンを沈殿させる工程、および
(f)任意に、イソプロパノールなどの非溶媒中で洗浄する工程を含む。
(a)エンドトキシンを含むキトサンを水性溶液中に溶解させる工程、
(b)水性溶液を界面活性剤と接触させ、エンドトキシンの含有量が減少した水不溶性の固形物と水性溶液を形成させる工程、および
(c)固体/液体分離手段により、固形物を水性溶液から分離する工程を含む。
(a)キトサン、キチン、キトサン誘導体、またはキチン誘導体をアルカリ溶液と接触させて、混合物を形成する工程と、
(b)該混合物を1時間未満放置する工程とを含む。
(a)キトサン、キチン、キトサン誘導体、またはキチン誘導体をアルカリ溶液と接触させて、混合物を形成する工程と、
(b)該混合物を直ちに乾燥させる工程とを含む。
1.キトサンのエンドトキシン試験用に、USP(米国薬局方)に詳述されている通りの抽出溶液(4.6mlの1M HClと45.4mlのエンドトキシンフリー水)を調製し、
2.0.1gの試験用キトサン生成物を9.9mlのUSP抽出溶液に加えて抽出し、37℃で48時間放置し、
3.48時間後、100μlの抽出物を0.9mlのエンドトキシンフリー水で希釈し、
4.上記の希釈液100μlを、100μlのチャールズリバー(Charles River)社製のエンドトキシンスペシフィック(Endotoxin Specific)(ES)緩衝液と混合する。
実施例1
50gのキトサンを、50gの1M NaOHと10分間混合した。結果として得られた、湿ったアルカリ性キトサン団粒(crumb)を、直ちに流動層乾燥機(fluid bed drier)内で40℃で乾燥した。
乾燥処理済みのアルカリ性キトサン:<5EU/g
実施例2
50gのキトサンを、50gの0.1M NaOHと10分間混合した。結果として得られた、湿ったアルカリ性キトサン団粒を、直ちに流動層乾燥機内で40℃で乾燥した。
乾燥処理済みのアルカリ性キトサン:16.3EU/g
実施例3
50gのキトサンを、50gの0.05M NaOHと10分間混合した。結果として得られた、湿ったアルカリ性キトサン団粒を、直ちに流動層乾燥機内で40℃で乾燥した。
乾燥処理済みのアルカリ性キトサン:20.0EU/g
実施例4
50gのキトサンを、50gの0.01M NaOHと10分間混合した。結果として得られた、湿ったアルカリ性キトサン団粒を、直ちに流動層乾燥機内で40℃で乾燥した。
乾燥処理済みのアルカリ性キトサン:<30EU/g
本発明の方法は拡大適用(scale up)することができ、より大きなバッチサイズでの製造も可能である。
低エンドトキシンのアルカリ性キトサンを酸と反応させて、中性のpHを有するキトサンまたはキトサン塩を製造する場合、酸性塩が副産物として生成される。この副産物の存在は、キトサン生成物の性能に影響を与える可能性がある。たとえば、副産物の量によっては生理食塩水中のキトサンの粘度に影響を与えることがある。
本発明の低エンドトキシンのアルカリ性キトサンを試験することにより、酸による処理がキトサン重合体の粘度に与える影響を明らかに示すことができる。ここでは、粘度は分子量の測定単位と考える。試験は次の手順によって行う。
b)600mlのビーカーに4.95gの酢酸を量って入れ、
c)490.05gの脱イオン化水をビーカーに加え、1%の酢酸溶液を495g調製し、
d)ビーカーを撹拌用プレート(stirrer plate)に載せ、攪拌器をオンにし(溶液の粘度が増加するにしたがい、撹拌速度を速くする)、
e)キトサン顆粒を酢酸溶液に加え、
f)顆粒がすべて溶解するまで定期的に溶液を確認し、必要ならば、溶液の粘度が増加するにしたがい、撹拌速度を速くし、
g)キトサン顆粒を酢酸溶液に加えた時点から計測して合計で24時間、溶液を放置し、
h)ブルックフィールド(Brookfield)粘度計にスピンドル64を取り付け、
i)スピンドルを10rpmにセットし、
j)スピンドルに示された目印までスピンドルを溶液に浸し、粘度計をオンにして安定するまで待ち、
k)選んだ時間間隔で、粘度(cPs)を記録する。
本発明の方法において、より低濃度のアルカリ溶液を使用することの効果は、3つの実験により試験することができる。実験では、(1)生理食塩水の試験サンプルへの浸透率、(2)凝血塊が形成される(血液が凝固する)までの時間、および(3)生体モデルでの上腹部断絶における止血割合に焦点を合わせる。
低エンドトキシンのアルカリ性キトサン、キチン、またはこれらの誘導体を製造する方法であって、
(a)キトサン、キチン、キトサン誘導体、またはキチン誘導体をアルカリ溶液と接触させて、混合物を形成する工程と、
(b)前記混合物を1時間未満放置する工程とを含む方法。
前記混合物を乾燥させる工程(c)をさらに含む(1)に記載の方法。
前記アルカリ溶液の濃度が約0.01Mから約1Mまでである(1)または(2)に記載の方法。
前記アルカリ溶液の濃度が約0.02Mから0.25Mまでである(3)に記載の方法。
前記アルカリ溶液の濃度が約0.1Mである(4)に記載の方法。
前記アルカリ溶液と、キトサン、キチン、キトサン誘導体、またはキチン誘導体とが、アルカリ溶液約10部に対してキトサン、キチン、キトサン誘導体、またはキチン誘導体約1部から、アルカリ溶液約1部に対してキトサン、キチン、キトサン誘導体、またはキチン誘導体約10部までの範囲内で存在する、前記いずれか一つのに記載の方法。
前記アルカリ溶液が、金属水酸化物、金属炭酸塩、金属重亜硫酸塩、金属過ケイ酸塩、共役塩基、および水酸化アンモニウムから選ばれるアルカリ成分またはアルカリ土類成分を単独でまたは組み合わせて含む、前記いずれか一つに記載の方法。
前記金属が、ナトリウム、カリウム、カルシウム、またはマグネシウムから選ばれる(7)に記載の方法。
前記アルカリ成分が、水酸化ナトリウム、水酸化カリウム、または炭酸ナトリウムから選ばれる(7)または(8)に記載の方法。
前記アルカリ溶液を前記キトサン、キチン、キトサン誘導体、またはキチン誘導体に対し噴霧するか、または前記キトサン、キチン、キトサン誘導体、またはキチン誘導体を前記アルカリ溶液と混合する、前記いずれか一つに記載の方法。
前記混合物を3分間未満放置する前記いずれか一つに記載の方法。
前記工程(b)が、前記工程(a)に続いて直ちに前記混合物を乾燥させることを含む(11)に記載の方法。
前記混合物を清潔な容器内に放置するか、および/または不活性雰囲気下で放置する、前記いずれか一つに記載の方法。
前記混合物が防腐剤をさらに含む前記いずれか一つに記載の方法。
前記防腐剤が、銀イオン、亜鉛イオン、クロルヘキシジン、またはこれらの組み合わせから選ばれる(14)に記載の方法。
(1)から(15)のいずれかに記載の方法によって得られる低エンドトキシンのアルカリ性キトサン、キチン、キトサン誘導体、またはキチン誘導体。
エンドトキシンの濃度が50EU/g未満であるアルカリ性キトサン、キチン、キトサン誘導体、またはキチン誘導体。
(1)から(15)のいずれかに記載の方法によって調製されるアルカリ性キトサンを酸と接触させる工程を含む、低エンドトキシンの中性キトサン、キトサン塩、またはキトサン誘導体を製造する方法。
前記アルカリ性キトサンを酸と接触させる工程を、(2)から(15)のいずれかに記載の前記乾燥工程(c)の前に行う(18)に記載の方法。
前記酸を前記アルカリ性キトサンに対し噴霧するか、または前記アルカリ性キトサンを前記酸と混合する(18)または(19)に記載の方法。
前記酸が、有機酸、カルボン酸、脂肪酸、アミノ酸、ルイス酸、一塩基酸、二塩基酸、多塩基酸、核酸、および鉱酸から単独でまたは組み合わせて選ばれる(18)から(20)のいずれかに記載の方法。
前記有機酸が、酢酸、酒石酸、クエン酸、アスコルビン酸、アセチルサリチル酸、グルコン酸、および乳酸から単独でまたは組み合わせて選ばれる(21)に記載の方法。
前記脂肪酸が、ミリストレイン酸、パルミトレイン酸、サピエン酸、オレイン酸、エライジン酸、バクセン酸、リノール酸、リノエライジン酸、α−リノレン酸、アラキドン酸、エイコサペンタエン酸、エルシン酸、ドコサヘキサエン酸、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、アラキジン酸、ベヘン酸、リグノセリン酸、およびセロチン酸から単独でまたは組み合わせて選ばれる(21)に記載の方法。
前記アミノ酸が、ヒスチジン、リシン、アスパラギン酸、グルタミン酸、グルタミン、グリシン、プロリン、およびタウリンから単独でまたは組み合わせて選ばれる(21)に記載の方法。
前記鉱酸が、塩酸、硫酸、および硝酸から単独でまたは組み合わせて選ばれる(21)に記載の方法。
前記酸の濃度が約1Mである(18)から(25)のいずれかに記載の方法。
前記酸が、前記酸と非溶媒とを含む酸液として存在する(18)から(26)のいずれかに記載の方法。
前記非溶媒が、乳酸エチル、酢酸エチル、酢酸メチル、エタノール、アセトン、80:20の割合のエタノールと水の混合物、またはこれらの混合物から単独でまたは組み合わせて選ばれる(27)に記載の方法。
酸液に対するキトサンの割合が約5:1から約1:5である(27)または(28)に記載の方法。
前記アルカリ性キトサンを前記酸と約5分間混合する(18)から(29)のいずれかに記載の方法。
前記反応物を乾燥させる工程をさらに含む(18)から(30)のいずれかに記載の方法。
(18)から(31)のいずれかに記載の方法により得られる低エンドトキシンの中性キトサン、キトサン塩、またはキトサン誘導体。
エンドトキシンの濃度が50EU/g未満である中性キトサン、キトサン塩、またはキトサン誘導体。
血液の流れを止めることを目的とする(32)に記載の低エンドトキシンのキトサン塩の使用。
血液の流れを止める止血剤として使用する(32)に記載の低エンドトキシンのキトサン塩。
生命に別状のない表部の出血用または生死に関わる出血用の創傷被覆材に使用する(32)に記載の低エンドトキシンのキトサン塩。
(32)に記載の低エンドトキシンのキトサン塩を含む止血用創傷被覆材。
血液の流れを止める方法であって、可能であれば創傷領域を任意に洗浄する工程と、請求項32に記載の低エンドトキシンのキトサン塩を含む止血用創傷被覆材を前記創傷領域に適用する工程と、ゲル状凝血塊が形成されるまで前記創傷領域に一定の圧力を加える工程とを含む方法。
本明細書および図面に実質的に記載され示される、低エンドトキシンのアルカリ性キトサン、中性キトサン、キトサン塩、またはキトサン誘導体、あるいはこれらの処理工程または方法。
Claims (1)
- 低エンドトキシンのアルカリ性キトサン、キチン、またはこれらの誘導体を製造する方法であって、
(a)キトサン、キチン、キトサン誘導体、またはキチン誘導体を0.01以上〜0.2M以下の濃度のアルカリ溶液と接触させて、混合物を形成する工程と、
(b)前記混合物を1時間未満で前記混合物を調製するのに要する時間放置する工程とを含む方法。
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