JP2022160584A - オキサリプラチンを含む経口用薬物送達組成物及びその製造方法 - Google Patents
オキサリプラチンを含む経口用薬物送達組成物及びその製造方法 Download PDFInfo
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- JP2022160584A JP2022160584A JP2022125209A JP2022125209A JP2022160584A JP 2022160584 A JP2022160584 A JP 2022160584A JP 2022125209 A JP2022125209 A JP 2022125209A JP 2022125209 A JP2022125209 A JP 2022125209A JP 2022160584 A JP2022160584 A JP 2022160584A
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- nanoemulsion
- oxaliplatin
- oxa
- drug delivery
- surfactant
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Abstract
Description
(a)オキサリプラチンに正電荷を帯びた胆汁酸誘導体を添加して、イオン結合複合体を形成する工程;(b)第1油相に第1界面活性剤と第1補助界面活性剤との混合物を添加する工程;(c)前記イオン結合複合体と前記工程(b)の混合物とを混合して、油中水型(water-in-oil;w/o)第1ナノエマルションを製造する工程;(d)前記w/o第1ナノエマルションに、第2界面活性剤と第2補助界面活性剤との混合物を添加して、水中油中水型(water-in-oil-in-water;w/o/w)第2ナノエマルションを製造する工程;を含むオキサリプラチンを含む経口用薬物送達組成物の製造方法を提供する。
経口吸収促進剤である胆汁酸誘導体はデオキシコール酸に正電荷を帯びたリシンを化学的に結合して、製造した。
重炭酸ナトリウムでpH7.0に調整した精製水に、オキサリプラチン及び前記実施例1で製造されたDCKをそれぞれ溶解した。前記オキサリプラチン水溶液を撹拌し、オキサリプラチン:DCKのモル割合が1:2になるようにDCK水溶液を徐々に添加して、イオン結合複合体を形成した。前記混合液を遠心分離した後、-70℃で凍結乾燥し、粉末状態のOXA/DCKイオン結合複合体を製造した。
w/o/w多重乳化ナノエマルションを製造するために、2段階の自発的多重乳化方法を用いており、1段階は以下の通りである。
w/o/w第2ナノエマルションはw/o第1ナノエマルションを油相とし、Cremophor ELとTranscutol HPの混合物を第2界面活性剤と第2補助界面活性剤の混合物(Smix,2)として、水相に油相を滴定する方法により製造した。
オキサリプラチン(OXA)とデオキシコール酸-リシン誘導体(DCK)との間のイオン結合複合体形成を確認するために、純粋なOXA、DCK、OXAとDCKの物理的混合物及びOXA/DCKイオン結合複合体を粉末X線回折分析器(PXRD)と示差走査熱量計(DSC)により分析し、その結果を図3に示した。
図2に示した疑似3相ダイヤグラムから透明なナノエマルション領域を確認した後、この領域から選択された8個の組成を対象として物理化学的性質を評価した。OXA/DCKイオン結合複合体及び5-FUを含むw/o/w第2ナノエマルションに分散されたw/o第1ナノエマルションの液滴直径、分散度(PDI)及び表面電荷(ゼータ電位)を動的光散乱測定装置(Zetasizer Nano ZS90;MalvernInstruments社製、UK)で測定し、液滴形態を透過電子顕微鏡(JEM-200;JEOL社製、Japan)で観察し、これを下記の表1及び図4に示した。
前記表1の組成で製造したOXA、OXA/DCKイオン結合複合体又は5-FUをそれぞれ含有したw/o/w第2ナノエマルションの膜透過性を人工腸管膜(PAMPA;BDBiosciences,SanJose,CA,USA)で評価した。対照群としてOXA、OXA/DCKイオン結合複合体及び5-FU水溶液を用いた。その結果を図5に示した。
Pe=-ln[1-CA(t)/Cequilibrium]/[A×(1/VD+1/VA)×t]
(式中、Pe:透過度(cm/s);A:有効フィルター面積(f×0.3cm2;f:フィルターの表面上の気孔(f=0.76));VD:供与体体積(0.2mL);VA:受容体体積(0.3mL);t:透過時間(秒);CA(t):時間tで受容体での薬物濃度;Cequilibrium:[CD(t)×VD+CA(t)×VA]/(VD+VA);CD(t):時間tで供与体の残存薬物濃度)
前記表1の組成で製造されたOXA、OXA/DCKイオン結合複合体又は5-FUをそれぞれ含有したw/o/w第2ナノエマルションの膜透過性を、Caco-2細胞単層膜を用いて評価した。対照群としてOXA、OXA/DCKイオン結合複合体及び5-FU水溶液を用いた。その結果を下記の表2に示した。
Papp=dQ/dt×1/(A×C0)
溶出試験は、米国薬局方溶出試験法第1法(回転検体通法)で、100rpm、37±0.2℃、0.1NHCl水溶液(pH1.2)培地又はリン酸塩緩衝液(pH6.8)500mLの条件で行った。
胆汁酸誘導体とのイオン結合複合体形成及びナノエマルション製剤によるOXA及び5-FUの経口吸収改善を評価するために、OXA又はOXA/DCKイオン結合複合体と5-FUを含む水溶液及びこれを含むナノエマルション剤形(前記表1の組成E、Smix,21:1)をラットに経口投与した。図7、下記表3及び表4は、ラットの血中薬物濃度-時間プロファイルとOXA及び5-FUの薬物動態パラメーターを示す。
CT26マウス大腸癌細胞をPBS(PH7.4)に1×106細胞/100μLの濃度で分散させた後、BALB/cマウスの背中部位に皮下注入した。14日後、腫瘍の大きさが70~100mm3のとき、無作為に10匹ずつ下記5個の群に分けた。
OXA-S(10mg/kgOXA水溶液、1日1回経口投与);
OXA/DCK-S(10mg/kgOXAに相当するOXA/DCKイオン結合複合体水溶液、1日1回経口投与);
5-FU-S(10mg/kg5-FU水溶液、1日1回経口投与);
OXA/DCK-5FU-NE(10mg/kgOXAに相当するOXA/DCKイオン結合複合体と10mg/kg5-FUを含むナノエマルション組成E(Smix、21:1)、1日1回経口投与)
腫瘍の大きさ=a2×b×0.52(a=幅、b=長さ)
Claims (14)
- (a)オキサリプラチンに正電荷を帯びた胆汁酸誘導体を添加して、イオン結合複合体を形成する工程;
(b)第1油相に第1界面活性剤と第1補助界面活性剤との混合物を添加する工程;
(c)前記イオン結合複合体と前記工程(b)の混合物とを混合して、油中水型(water-in-oil、w/o)第1ナノエマルションを製造する工程;
(d)前記油中水型(w/o)第1ナノエマルションに、第2界面活性剤と第2補助界面活性剤との混合物を添加して、水中油中水型(water-in-oil-in-water、w/o/w)第2ナノエマルションを製造する工程;
を含むことを特徴とするオキサリプラチンを含む経口用薬物送達組成物の製造方法。 - 前記胆汁酸誘導体は、Nα-デオキシコリル-L-リシル-メチルエステル(DCK)であることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記第1油相は、シリコーンオイル、エステル系オイル、ハイドロカーボン系オイル、プロピレングリコールモノカプリレート(Capryol 90)、プロピレングリコールジカプリロカプレート(Labrafac PG)、オレオイルマクロゴール-6グリセリド(Labrafil M1944 CS)、ラウロイルマクロゴール-6グリセリド(Labrafil M2130 CS)、リノレオイルマクロゴール-6グリセリド(Labrafil M2125 CS)、重鎖トリグリセリド(Labrafac)、オレイン酸、ステアリン酸、ベヘン酸グリセリン(Compritol 888)、グリセロールモノステアレート及びヒマシ油からなる群から選択されるいずれか一つ又は1種以上であることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記第1及び第2界面活性剤は、互いに独立して、ポロキサマー(poloxamer)、カプリロカプリルマクロゴール-8グリセリド(Labrasol)、クレモフォール(Cremophor)、グリセロールモノカプリロカプレート(Capmul MCM)、ラウロイルマクロゴール-32グリセリド(Gelucire 44/14)、ソルトロール(Solutrol)、ポリソルベート(Tween)及びソルビタンモノラウレート(Span)からなる群から選択されるいずれか一つ又は1種以上であることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記第1及び第2補助界面活性剤は、互いに独立して、ジエチレングリコールモノエチルエーテル(Transcutol HP)、ポリソルベート、ポリエチレングリコール、ブチレングリコール、プロピレングリコール、エタノール及びイソプロパノールからなる群から選択されるいずれか一つ又は1種以上であることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記胆汁酸誘導体は、オキサリプラチン1モルに対して、0.5~5モル含まれることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記w/o/w第2ナノエマルション内油中水型(w/o)第1ナノエマルションは、組成物全重量に対して、1~40重量%含まれることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記第1界面活性剤と第1補助界面活性剤との混合物及び第2界面活性剤と第2補助界面活性剤との混合物は、組成物全重量に対して、5~90重量%含まれることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記第1及び第2補助界面活性剤は、それぞれ第1及び第2界面活性剤に対して、互いに独立して、1:0.1~1:10の重量比で混合されることを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記工程(a)において、単糖類、多糖類、食物繊維、ガム類、界面活性剤又はタンパク質から選択される凝集防止剤をさらに含むことを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法
- 前記凝集防止剤は、オキサリプラチン1重量部に対し、0.1~100重量部含まれることを特徴とする請求項10に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記w/o第1ナノエマルションは、内部水相に5-フルオロウラシル(5-FU)又はロイコボリンから選択される親水性有効成分をさらに含むことを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 前記工程(d)において、w/o/w第2ナノエマルションは、油相に難溶性抗癌剤、クルクミン、ケルセチン、クルクミン又はケルセチンを有効成分として含有する天然抽出物、及びこれらの混合物から選択される脂溶性有効成分をさらに含むことを特徴とする請求項1に記載のオキサリプラチンを含む経口用薬物送達組成物の製造方法。
- 請求項1~13に記載の製造方法によって製造されたオキサリプラチンを含む経口用薬物送達組成物。
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EP (1) | EP3639859A4 (ja) |
JP (2) | JP2020522580A (ja) |
KR (1) | KR101895237B1 (ja) |
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KR102216578B1 (ko) * | 2019-09-05 | 2021-02-17 | 주식회사 아이큐어비앤피 | 테리파라타이드를 포함하는 경구용 약학 조성물 및 이의 제조방법 |
KR20210092883A (ko) | 2020-01-17 | 2021-07-27 | 문창상 | 라이신-데옥시콜산 염의 제조 방법 |
CN111658613B (zh) * | 2020-07-13 | 2021-02-09 | 深圳大学 | 一种w/o/w型不饱和古罗糖醛酸纳米乳及其制备方法 |
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US20030180352A1 (en) * | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
KR20010100194A (ko) * | 2000-03-13 | 2001-11-14 | 박호군 | 여러 가지 물질의 가용화용 조성물과 제형 및 그들의제조방법 |
KR20030021706A (ko) * | 2001-09-07 | 2003-03-15 | 주식회사 엘지생활건강 | 미녹시딜을 함유한 w/o/w 다중 에멀젼 및 이의 제조방법 |
KR101102935B1 (ko) * | 2009-05-14 | 2012-01-10 | 한불화장품주식회사 | 다중 지질 마이크로캡슐 및 이를 함유하는 화장료 조성물 |
RU2563997C2 (ru) * | 2009-09-21 | 2015-09-27 | Джей ДаблЮ ФАРМАСЬЮТИКАЛ КОРПОРЭЙШН | Наночастицы оксалиплатина и способ их получения |
GB201019434D0 (en) * | 2010-11-17 | 2010-12-29 | Isis Innovation | Sonosensitive nanoparticles |
KR101440425B1 (ko) * | 2012-01-27 | 2014-09-17 | 한국콜마주식회사 | 음이온성 계면활성제를 포함하는 수중유중수형 다중에멀젼 상 화장료 조성물 및 그 제조방법 |
KR20150010472A (ko) | 2013-07-19 | 2015-01-28 | 한국전자통신연구원 | 전력 정류 소자 |
WO2015058111A1 (en) * | 2013-10-17 | 2015-04-23 | The Brigham And Women's Hospital, Inc. | Cationic nanoparticles for co-delivery of nucleic acids and thereapeutic agents |
KR101593531B1 (ko) * | 2014-03-06 | 2016-02-15 | 한국식품연구원 | W/o/w형 다중 에멀젼의 제조방법 |
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- 2017-11-30 WO PCT/KR2017/013958 patent/WO2018230788A1/ko unknown
- 2017-11-30 CN CN201780091976.6A patent/CN110740755A/zh active Pending
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KR101895237B1 (ko) | 2018-09-07 |
WO2018230788A1 (ko) | 2018-12-20 |
EP3639859A4 (en) | 2021-03-31 |
CN110740755A (zh) | 2020-01-31 |
EP3639859A1 (en) | 2020-04-22 |
US11452705B2 (en) | 2022-09-27 |
JP2020522580A (ja) | 2020-07-30 |
US20210290586A1 (en) | 2021-09-23 |
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