JP2021512062A - ベルベリンを含む組成物 - Google Patents
ベルベリンを含む組成物 Download PDFInfo
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- JP2021512062A JP2021512062A JP2020540484A JP2020540484A JP2021512062A JP 2021512062 A JP2021512062 A JP 2021512062A JP 2020540484 A JP2020540484 A JP 2020540484A JP 2020540484 A JP2020540484 A JP 2020540484A JP 2021512062 A JP2021512062 A JP 2021512062A
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Abstract
Description
a)ベルベリン(BBR);
b)エンドウ豆タンパク質;
c)一つ以上の界面活性剤;および
d)任意選択で、ヴィティス(Vitis)種またはシトラス(Citrus)種の植物抽出物またはそれらの組み合わせ。
BBRが、エンドウ豆タンパク質、界面活性剤およびヴィティス種の抽出物、好ましくはVitis vinifera抽出物、および/またはシトラス種の抽出物、好ましくはCitrus vinifera抽出物と連合している場合、さらなる増加が観察される。理論に束縛されるものではないが、少なくとも1つの界面活性剤の存在はBBR、エンドウ豆タンパク質、ならびにヴィティスおよび/またはシトラス種抽出物(使用される場合)の間の相乗的相互作用を促進し、これは次いで、BBRの溶解性および吸収の増加を生じると考えられる。
a)ベルベリン(BBR);
b)エンドウ豆タンパク質;
c)一つ以上の界面活性剤;および
d)任意選択で、ヴィティス(Vitis)種またはシトラス(Citrus)種の植物抽出物またはそれらの組み合わせ。
「エンドウ豆タンパク質」という表現は、乾燥エンドウ豆(Pisum sativum)からの水性抽出プロセスによって得られるタンパク質と同一視する。
エンドウ豆タンパク質に加えて、ヴィティス種抽出物および/またはシトラス種抽出物を含有する本発明による組成物において、BBRまたは純粋なBBRを含有する抽出物と、エンドウ豆タンパク質およびヴィティス種抽出物および/またはシトラス種抽出物の総重量との間の重量比は、1:1w/w〜5:1w/wの範囲である。
エンドウ豆タンパク質とヴィティス種抽出物および/またはシトラス種抽出物との間の比は、1:3w/w〜3:1w/wの範囲である。
a)BBR;
b)エンドウ豆タンパク質;
c)一つ以上の界面活性剤;
d)および任意選択で、ヴィティス種またはシトラス種の植物抽出物またはそれらの組み合わせ。
・微結晶性セルロース、リン酸カルシウム、炭酸カルシウム、マンニトール、マルトデキストリン、イソマルトまたはそれらの組み合わせなどの不溶性および可溶性希釈剤;
・二酸化ケイ素、タルク、ステアリン酸、ステアリン酸マグネシウム、またはそれらの組み合わせなどの潤滑剤および/または流動促進剤。
a−1)界面活性剤または界面活性剤の混合物を、好ましくはエチルアルコール、酢酸エチルおよびアセトンから選択される50〜100容量の有機溶媒中に、溶液または均一な分散液が得られるまで可溶化または分散させる;
b−1)工程a−1)で得られた溶液または分散液に、BBR、および任意選択でヴィティス種抽出物および/またはシトラス種抽出物を添加し、好ましくは40℃〜70℃、より好ましくは60℃の範囲の温度に加熱して、分散液を得る;
c−1)工程b−1)で得られた分散液を室温に冷却し、分散液が得られるまで、好ましくは約10〜15分間、撹拌下でエンドウ豆タンパク質を添加する;
d−1)任意選択で工程c−1)で得られた分散液に希釈剤、好ましくは微晶質セルロース、または希釈剤の混合物を添加する;
e−1)工程c−1)で得られた混合物から、好ましくは50℃〜75℃、より好ましくは≦65℃の範囲の温度を維持し、好ましくは100〜500mbarの間での低圧蒸発で溶媒を除去し、任意選択で、60〜65℃の温度に設定されたストーブ内で真空下での乾燥を、好ましくは<1.2質量%の溶媒残渣が得られるまでで停止させる;
f−1)工程e−1)の終わりに得られた組成物を10メッシュ篩上で較正し、任意選択で、好ましくはステアリン酸、ステアリン酸マグネシウムおよび二酸化ケイ素、好ましくは二酸化ケイ素から選択される潤滑剤および/または流動促進剤を添加する。
a−2)界面活性剤または界面活性剤の混合物を、好ましくはエチルアルコール、酢酸エチルおよびアセトン、好ましくはエチルアルコールから選択される5〜10容量の有機溶媒中に、溶液または均一な懸濁液が得られるまで可溶化または分散させる;
b−2)工程a−2)で得られた溶液または懸濁液とは別に、BBRを含有する抽出物をエンドウ豆タンパク質、任意選択でヴィティス種抽出物および/またはシトラス種抽出物、および希釈剤、好ましくは微結晶セルロースと、均一な混合物が得られるまで、典型的には約5分間混合する;
c−2)工程b−2)で得られた混合物を工程a−2)で得られた溶液または懸濁液に加えて混合物を得、得られた混合物を約10〜15分間撹拌下に保つ;
d−2)工程c−2)で得られた混合物を、真空下、約60〜65℃の温度で、<1.2質量%の残留溶媒含量が得られるまで、ストーブ乾燥する;
e−2)工程d−2)の終わりに得られた組成物を10メッシュ篩上で較正し、任意選択で、好ましくはステアリン酸、ステアリン酸マグネシウムおよび二酸化ケイ素、好ましくは二酸化ケイ素から選択される1つ以上の滑沢剤および/または流動促進剤を添加する。
以下の項に記載される実施例は、本発明をさらに説明する。
約50%のBBR含量を有するBerberis aristataの根からの植物抽出物および純粋なBBRは、Indian Herbs Extractions,Ramnagarから得た。
実施例1 50質量%に滴定したBBR抽出物、エンドウ豆タンパク質およびレシチンを含有する組成物
50質量%BBR抽出物 60.0%
エンドウ豆タンパク質 15.0%
レシチン 14.0%
ヒドロキシプロピルセルロース 5.0%
二酸化ケイ素 2.0%
ポリソルベート80 4.0%
組成物は、以下の工程を含む、以下の方法(P−1)によって得られた。
工程1 ポリソルベート80およびヒドロキシプロピルセルロースを、溶液が得られるまでエチルアルコールに溶解した。
工程2 50質量%に滴定したBBR抽出物を、磁気撹拌下で工程1で得られた溶液に添加し、分散液が得られるまで60℃に加熱した。
工程3 工程2で得られた分散液に、磁気撹拌下でレシチンを添加し、60℃に加熱した。
工程4 工程3で得られた分散液を室温まで冷却し、エンドウ豆タンパク質を添加して分散液を得た。
工程5 温度を65℃以下に維持しながら、工程4で得られた分散液から溶媒を低圧蒸発によって除去した。
工程6 工程5で得られた生成物を、エチルアルコール残渣が1.2%未満になるまで65℃で真空下でストーブ乾燥した。
工程7 工程6で得られた生成物を10メッシュ篩で較正し、50メッシュ篩を通して予備篩分けした二酸化ケイ素を添加した。
50質量%に滴定したBBR抽出物 54.6%
エンドウ豆タンパク質 13.2%
レシチン 12.7%
Citrus bergamiaエキス 9.1%
ヒドロキシプロピルセルロース 5.0%
二酸化ケイ素 1.8%
ポリソルベート80 3.6%
この組成物は実施例1に記載した方法に従って得たが、Citrus bergamia抽出物も工程2で添加した点が異なる。
50質量%BBR抽出物 54.6%
エンドウ豆タンパク質 13.2%
レシチン 12.7%
Vitis vinifera種抽出物 9.1%
ヒドロキシプロピルセルロース 5.0%
二酸化ケイ素 1.8%
ポリソルベート80 3.6%
組成物は、Vitis vinifera種抽出物も工程2で添加した点を除いて、実施例1に記載の方法に従って得た。
実施例1の組成物 500.0mg
リン酸二カルシウム二水和物 200.0mg
マンニトール 150.0mg
ポリビニルポリピロリドン 30.0mg
ステアリン酸マグネシウム 10.0mg
コロイドシリコンジオキシド 10.0mg
メチルセルロースベース塗料 20.0mg
実施例5 硬質ゼラチンカプセル
実施例3の組成物 550.0mg
結晶セルロース 60.0mg
ステアリン酸マグネシウム 10.0mg
コロイドシリコンジオキシド 10.0mg
実施例6 水分散性顆粒
実施例2の組成物 550.0mg
マルトデキストリン 1200.0mg
フルクトース 425.0mg
グアーガム 200.0mg
オレンジ風味 100.0mg
スクラロース 20.0mg
コロイドシリコンジオキシド 5.0mg
評価
模擬生体液中での溶解度試験
溶解度試験は、等量のBBRを含有するサンプルを比較することによって行った。
装置:Waters Acquity UPLC H-Class System.
権限ソフトウェア(Empower System Enterprise Client/Server)。
カラム:固定相:Acquity UPL CSH C18;寸法:l=100mm;内径=2.1mm;粒径:1.7μm;製造業者:Waters
移動相:溶媒A:0.5%リン酸(w/v);溶媒B:アセトニトリル
直線勾配
可溶化溶媒:80%メタノール
ブランク溶液:80%メタノール
試料溶液:200ml中30mg(図1の〜0.15mg/mlの典型的な試料のクロマトグラム)。
標準溶液:200mlのメタノール中の10mgの純粋な参照BBR(標準溶液〜0.05mg/ml、図2の典型的なクロマトグラム)。
溶解度試験は、以下に報告するように調製した空腹状態模擬胃液(Fasted-State Simulated Gastric Fluid)(FaSSGF)を溶媒として用いて行った。
1)FaSSGF用NaCl/HCl溶液の調製(1リットル):
2gのNaClを0.9lの精製水に溶解し、HClでpHを1.6に調整し、混合物を精製水(1リットル)で容量調整した。
2)0.06gの粉末* (FaSSGF-Biorelevant培地)を、室温で約500mlのNaCl/HCl溶液に添加し、NaCl/HCl溶液で容量調整し(1l)、透明なすぐに使用できる液体を得た。
註:* 最終タウロコール酸ナトリウム0.08mM、最終レシチン0.02mM
試験結果を下記表2に示す:
エンドウ豆タンパク質の添加は明らかに、溶解度のさらなる増加を生じる。Citrus bergamia抽出物またはVitis vinifera種抽出物の添加は、BBRの溶解度のさらなる増加を生じる。特に、BBRの溶解度はBBRをエンドウ豆タンパク質およびレシチンのみと組み合わせた場合には約3倍増加するが、Citrus bergamia抽出物またはVitis vinifera種抽出物とも組み合わせた場合には約4倍増加する。これらの知見は、本発明による組成物がその腸吸収に対する最大の障害を構成する水性媒体中のBBRの溶解度を増加させることを実証する。
トランスウェルインサート上の機能的単層として編成されたCaco2ヒト腸腺癌細胞(ATCC、HTB―37TM)に基づくヒト腸上皮のin vitroモデルを用いて、BBRの吸収と生物学的利用能を測定した。トランスウェルインサートの特徴は、頂端側(または管腔側)と基底側(または漿膜側)の2つのコンパートメントであり、微小孔性の膜で隔てられている。
実施例1に記載の組成物を用いて得られる吸収の増加を評価するために、ラットに対して薬物動態試験を行った。試験は、3匹のSprague Dawleyラットに100mg/kgの純粋なBBRに相当する1000mg/kgの実施例1に従った組成物、および100mg/kgの純粋なBBRを3匹のラットに経口投与することによって行った。生成物を、可溶化剤として1重量%のメチルセルロースと共に蒸留水中で投与した。次いで、血液サンプルを、15分、30分、1時間、2時間、4時間および6時間後に、ヘパリン処理した試験管中で0.5mlの体積に達するように、後頭静脈洞から採取した。
これらのデータは溶解度試験の予測値を実証し、インビボでの薬物動態パラメーターおよび生物学的利用能の改善を確認する。
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Claims (15)
- a)ベルベリン(BBR);
b)エンドウ豆タンパク質;
c)一つ以上の界面活性剤;および
d)任意選択で、ヴィティス(Vitis)またはシトラス(Citrus)種の植物抽出物またはそれらの組み合わせ;
を含む組成物。 - ベルベリンが、Berberis aristata、Coptis chinensisまたはHydrastis Canadensisの根の水性抽出物の形態で使用される、請求項1に記載の組成物。
- 前記水性抽出物がBerberis aristataの根から得られる、請求項2に記載の組成物。
- 前記抽出物が30質量%〜70質量%の範囲の量のベルベリンを含有する、請求項2または3に記載の組成物。
- 前記抽出物が50質量%に等しい量のベルベリンを含有する、請求項4に記載の組成物。
- ベルベリンが、85質量%を超えるベルベリン含有量を有する抽出物の形態で使用される、請求項1に記載の組成物。
- 前記界面活性剤が、リン脂質、スクロースエステル、ポリソルベート、ポリオキシエチレンヒマシ油誘導体、D−α−トコフェリル−ポリエチレングリコールスクシネートまたはそれらの混合物から選択される、請求項1〜6のいずれか1項に記載の組成物。
- 前記界面活性剤がレシチンである請求項7に記載の組成物。
- レシチンが大豆レシチンまたはヒマワリレシチンで請求項8に記載の組成物。
- Vitis vinifera種抽出物またはCitrus bergamia抽出物またはそれらの組み合わせを含む、請求項1〜9のいずれか1項に記載の組成物。
- 薬剤として使用するための、請求項1〜10のいずれか1項に記載の組成物。
- 脂質異常症、高コレステロール血症、メタボリックシンドロームおよび心血管疾患の予防および/または治療に使用する、請求項1〜10のいずれか一項に記載の組成物。
- 請求項1〜10のいずれか1項に記載の組成物、または請求項1〜10のいずれか1項に記載の組成物および少なくとも1つの薬学的に許容される賦形剤を含む製剤、の製造方法であって、該方法は、界面活性剤の溶液または分散液の調製と、1つ以上の連続工程において、BBR、エンドウ豆タンパク質、任意選択でヴィティス(Vitis)種の抽出物および/またはシトラス(Citrus)種の抽出物、および任意選択で少なくとも1つの薬学的に許容される賦形剤の添加とを含む製造方法。
- 請求項13に記載の方法によって得ることができる組成物または製剤。
- 請求項1〜10のいずれか1項に記載の組成物、および少なくとも1つの適切な薬学的に許容される賦形剤を含む製剤。
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HUE063267T2 (hu) | 2024-01-28 |
PT3746054T (pt) | 2023-09-14 |
CN111787909B (zh) | 2023-04-28 |
FI3746054T3 (fi) | 2023-09-05 |
IL276144A (en) | 2020-09-30 |
WO2019150225A1 (en) | 2019-08-08 |
US11786513B2 (en) | 2023-10-17 |
RU2020128327A (ru) | 2022-03-02 |
KR20200118456A (ko) | 2020-10-15 |
RU2020128327A3 (ja) | 2022-03-02 |
SI3746054T1 (sl) | 2023-09-29 |
CN111787909A (zh) | 2020-10-16 |
EP3746054A1 (en) | 2020-12-09 |
MX2020008125A (es) | 2020-09-18 |
BR112020015706A2 (pt) | 2020-12-08 |
SG11202006513UA (en) | 2020-08-28 |
JP7490557B2 (ja) | 2024-05-27 |
US20200368215A1 (en) | 2020-11-26 |
CA3087842A1 (en) | 2019-08-08 |
EP3746054B1 (en) | 2023-06-14 |
PL3746054T3 (pl) | 2023-10-16 |
IL276144B1 (en) | 2024-06-01 |
AU2019213699A1 (en) | 2020-07-23 |
DK3746054T3 (da) | 2023-08-07 |
ES2955586T3 (es) | 2023-12-04 |
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