JP7284743B2 - ケルセチンを含む粉末固体分散体、その調製方法およびその製剤 - Google Patents
ケルセチンを含む粉末固体分散体、その調製方法およびその製剤 Download PDFInfo
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- JP7284743B2 JP7284743B2 JP2020500740A JP2020500740A JP7284743B2 JP 7284743 B2 JP7284743 B2 JP 7284743B2 JP 2020500740 A JP2020500740 A JP 2020500740A JP 2020500740 A JP2020500740 A JP 2020500740A JP 7284743 B2 JP7284743 B2 JP 7284743B2
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- quercetin
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- carrier
- phospholipid
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Description
Hong-Bo Yang、et al(2017) Joint International Conference on Materials Science and Engineering Application、April 2017、pages 1-7)はテトラヒドロフラン中に1:2の重量比でケルセチンおよびリン脂質を溶解し、撹拌し、濾過し、真空下50℃で乾燥することによる、リン脂質中のケルセチンの固体分散体の調製を開示している。X線はケルセチン自体が結晶性固体であることを示唆するが、固体分散体のX線分析は固体分散体中にケルセチンが非晶質形態で存在することを示す。
本発明によれば、用語「非常に溶ける(very soluble)」および用語「自由に溶ける(freely soluble)」はヨーロッパ薬局方5.0に定義されるように、以下のスキームで報告される意味を有する。
a)ケルセチンの有機溶媒溶液[溶液(S1)]を調製する工程;
b)工程a)で使用したのと同じ溶媒中のリン脂質の溶液/懸濁液[溶液または懸濁液(S2)]を調製する工程;
c)工程a)で得られたケルセチンの溶液を工程b)で得られたリン脂質の溶液/懸濁液と接触させて、さらなる溶液または懸濁液[懸濁液または溶液(S3)]を準備する工程;
d)工程c)で得られた溶液または懸濁液に、水に非常に溶けるないし自由に溶ける担体を添加する工程、
e)真空下または噴霧乾燥下で溶媒を除去して、粉末固体分散体を形成する工程。
a1)5重量%未満の水を含む有機溶媒中のケルセチンの溶液[溶液(S1)]を調製する工程;
b1)溶液(S1)にリン脂質および非常に溶けるから水担体に自由に溶ける担体を添加して、溶液中にケルセチン、リン脂質および担体を含む溶液または懸濁液[溶液または懸濁液(S3)]中に準備する工程、
c1)真空下または噴霧乾燥下で溶媒を除去して、粉末固体分散体を形成する工程。
ケルセチン二水和物375gをエチルアルコール13Lに添加し、次いで60℃で加熱し、完全に溶解するまで約15分間混合した。
ケルセチン二水和物350gを酢酸エチル12 Lに加え、次いで60℃で加熱し、完全に溶解するまで約15分間混合した。
実施例1で得られた粉末固体分散体を、(未配合の、遊離形態の)ケルセチン二水和物と比較して、DSCによって分析した。分析は、Mettler DSC1 Systemを用いて行った。熱流は、50ml/分の窒素流下で、ピンホールを有する閉じたアルミニウムるつぼ(40μl体積)を使用して、線形加熱速度(10℃/分)で30~300℃で記録した。約5~10mgの粉末を各測定に使用した。熱プロファイルは、専用のソフトウェアによって取得し、綿密化した。
実施例1で得られたケルセチン二水和物、ケルセチン粉末固体分散物、および前記固体分散物の成分の機械的(物理的)混合物を、高過剰の分析物の存在下で、以下の模擬胃腸液を使用して、比較溶解度実験に供した:
空腹時模擬胃液;
空腹時模擬腸液;
摂食状態模擬腸液。
等量のケルセチンを実験中に使用した。
ケルセチン二水和物、実施例1のケルセチン粉末固体分散物および機械的(物理的)混合物を磁気撹拌下に2時間保持した。
上清を濾過し、ケルセチン濃度をHPLC分析によって計算した。
これらの溶解度研究の結果を以下の表1に報告する:
空腹時条件下の健常ボランティアにおける単回用量無作為化クロスオーバー薬物動態試験を、500mgの(未製剤)ケルセチン二水和物、500mgのケルセチン(40%)粉末固体分散体(200mgのケルセチン二水和物に相当)および250mgのケルセチン(40%)粉末固体分散体(100mgのケルセチン二水和物に相当)を含有するフィルムコーティング錠を用いて行った。
定量組成 (mg/錠)
ケルセチン固体分散体(実施例1) 250.0 mg
リン酸二カルシウム二水和物 270.0 mg
マンニトール 180.0 mg
クロスカルメロースナトリウム 40.0 mg
二酸化ケイ素 15.0 mg
タルク 15.0 mg
ステアリン酸マグネシウム 10.0 mg
フィルムコーティング 20.0 mg
実施例7:ケルセチン粉末固体分散体(軟ゼラチンカプセル)を含有する製剤
定量組成 (mg/錠)
ケルセチン固体分散体(実施例2) 300.0 mg
亜麻仁油 345.0 mg
蜜蝋 10.0 mg
レシチン液 5.0 mg
実施例8:ケルセチン粉末固形分散体(分散用顆粒)を含有する製剤
定量組成 (mg/錠)
ケルセチン固体分散体(実施例1) 500.0 mg
マルトデキストリン 2330.0 mg
グアーガム 300.0 mg
風味 200.0 mg
クエン酸 155.0 mg
スクラロース 15.0 mg
Claims (19)
- ケルセチン、リン脂質、および水に非常に溶けるないし自由に溶ける、マルトデキストリン;単糖および二糖;多価アルコール;可溶性オリゴ糖および多糖からなる群から選択される担体を含む粉末固体分散体の調製方法であって、
該方法は、ケルセチン、リン脂質および前記担体を加熱しながら、無水有機溶媒に溶解または懸濁させ、次いで該溶媒を除去して粉末固体分散体を得ることを含み、
該方法は、前記無水有機溶媒として5重量%未満の水を含む有機溶媒を使用して実施され、水に溶解する工程を全く含まない、粉末固体分散体の調製方法:
ただし、前記非常に溶けるとは、15℃~25℃の間の温度における溶質1g当たりの溶剤の量(ミリリットル)が1未満であることを意味し、前記自由に溶けるとは、15℃~25℃の間の温度における溶質1g当たりの溶剤の量(ミリリットル)が1~10であることを意味する。 - 以下の工程を含み、工程a)~工程d)が加熱下で行われる、請求項1に記載の方法:
a)前記5重量%未満の水を含む有機溶媒中のケルセチンの溶液を調製する工程;
b)工程a)で使用した溶媒と同じ溶媒中でリン脂質の溶液/懸濁液を調製する工程;
c)工程a)で得られたケルセチンの溶液を、工程b)で得られたリン脂質の溶液/懸濁液と反応させる工程;
d)工程c)で得られた混合物に、前記担体を添加する工程;および
e)真空下または噴霧乾燥下で溶媒を除去して、粉末固体分散体を形成する工程。 - 工程a)~工程d)が40℃~80℃の範囲の温度で実施される、請求項2に記載の方法。
- 以下の工程を含み、工程a1)および工程b1)が加熱下で行われる、請求項1に記載の方法:
a1)前記5重量%未満の水を含む有機溶媒中のケルセチンの溶液[溶液(S1)]を調製する工程;
b1)溶液(S1)にリン脂質および前記担体を添加して、前記溶媒中の、ケルセチン、リン脂質および担体の溶液または懸濁液[溶液または懸濁液(S3)]を準備する工程;および
c1)真空下または噴霧乾燥下で溶媒を除去して、粉末固体分散体を形成する工程。 - 工程a1)および工程b1)が40℃~80℃の範囲の温度で実施される、請求項4に記載の方法。
- ケルセチン対リン脂質の重量比が5:1~1:1の範囲である、請求項1~5のいずれか1項に記載の方法。
- ケルセチン対リン脂質の重量比が2:1~1:1の範囲である、請求項6に記載の方法。
- ケルセチンがケルセチン二水和物である、請求項1~7のいずれか1項に記載の方法。
- 前記リン脂質が、大豆、ひまわりまたは卵由来のレシチン、ホスファチジルコリン、ホスファチジルセリン、ホスファチジルエタノールアミン、またはそれらの混合物からなる群から選択され、前記リン脂質に含まれるアシル基は同一であるかまたは異なり、大部分がパルミチン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸に由来する、請求項1~8のいずれか1項に記載の方法。
- 単糖および二糖が、スクロースおよびフルクトースからなる群から選択される、請求項1~9のいずれか1項に記載の方法。
- 前記多価アルコールが、マンニトール、ソルビトール、キシリトールからなる群から選択される、請求項1~10のいずれか1項に記載の方法。
- 前記可溶性オリゴ糖および多糖がデキストランまたはプルランである、請求項1~11のいずれか1項に記載の方法。
- 前記担体が、マルトデキストリンである、請求項1~9のいずれか1項に記載の方法。
- ケルセチン対担体重量比が1:5~5:1の範囲である、請求項1~13のいずれか1項に記載の方法。
- ケルセチン対担体重量比が1:2~3:1の範囲である、請求項14に記載の方法。
- 前記無水有機溶媒が、エチルアルコール、イソプロピルアルコール、n-プロピルアルコール、n-ブタノール、酢酸エチル、アセトンからなる群から選択される、請求項1~15のいずれか1項に記載の方法。
- 前記粉末固体分散体の平均粒度分布が100μm~300μmである、請求項1~16のいずれか1項に記載の方法。
- 前記粉末固体分散体が、8.9±0.2、13.5±0.2、26.0±0.2、および27.8±0.2 2θ角(CuKα λ=1.5419Å)にピークを有するX線回折パターンにより特徴づけられる、請求項1~17のいずれか1項に記載の方法。
- 請求項1~18のいずれか1項に記載の方法により得られる粉末固体分散体と、1つ以上の薬学的および食品許容の賦形剤とを含む製剤を調製することを含む、経口投与のための製剤の調製方法。
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