JP5491724B2 - 生物学的利用能を向上した医薬組成物 - Google Patents
生物学的利用能を向上した医薬組成物 Download PDFInfo
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- JP5491724B2 JP5491724B2 JP2008298513A JP2008298513A JP5491724B2 JP 5491724 B2 JP5491724 B2 JP 5491724B2 JP 2008298513 A JP2008298513 A JP 2008298513A JP 2008298513 A JP2008298513 A JP 2008298513A JP 5491724 B2 JP5491724 B2 JP 5491724B2
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-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
a)溶解度の低い薬物を可溶性の塩またはエステルに変換する方法。
b)薬物の溶解性を高めるために、粒径を小さくし、全表面積を増やす方法。これは通常機械的処理によって実施される。
c)可溶化剤を添加することにより、水への薬物の溶解度を高める方法。
d)1つ以上の活性成分と賦形剤とを混合することで、均一に分散された固溶体系を生産する「固溶体」(SDS)技術。一般に使用される方法は、溶媒法、溶融法、溶媒噴霧法、および研削法である。この技術の利点は、薬物の溶解および生物学的利用能を向上させることである。
溶解試験は、次の手順で実施した。
機器:Logan UDT−804(USA)
溶媒:900mlの蒸留水に、37%濃HClを8.5ml添加し、その後、この溶液を均一に撹拌および混合し、総体積を1Lに到達させることによって500mlの0.1N HCL溶液を準備した。
USP装置2(パドル):50rpm
温度:37±0.5℃
サンプリング時間(分):7、15、30、45、60、90、および120
手順:
i.500mlの0.1N HCl溶液を6つの各溶解容器に注ぎ、予熱した。水槽の温度を37±0.5℃に維持し、溶解試験器の撹拌装置を必要に応じて設定した。
ii.溶解溶媒の温度を温度計で測定した。温度が37±0.5℃に達すると、溶解試験を実施した。
iii.各製剤のカプセル1つを、溶解容器の中へ落とした。
iv.次の時点において試料を収集した:7分、15分、30分、45分、60分、90分、および120分。
v.試料は、0.45μmのボアサイズを有するPVDFでできたフィルタを用いて濾過し、次に、サンプルの薬物濃度をHPLCで測定した。
i.移動相: 蒸留水:アセトニトリル:メチルtert−ブチルエーテル:リン酸(v/v/v/v)=440:510:45:1の混合物を調製した。この混合物は、0.45μmのボアサイズを有するナイロン66でできたフィルタを用いて濾過した。この混合物を、液体に含有された気体が除去されるように、超音波処理機によって、少なくとも30分間にわたって超音波処理した。
ii.ポンプ(ポンプL−7100、HITACHI、日本)−流量:1.5ml/分。
iii.検出器(UV検出器L−7400、HITACHI、日本)−波長:210nm。
iv.試料バイアルを、オートサンプラー(オートサンプラーL−7200、HITACH、日本)の試料棚の上に置き、注入量を20μlに設定した。
v.カラム: USPパッキングL1を含む4.6mm×250cmカラム
vi.カラム温度:カラムを80℃のカラムオーブンに置いた。
0.1N HCl溶液(人工胃液)中の実施例3から実施例8の製剤によって形成されたマイクロエマルジョンの粒径を、次の手順で測定した:
i.500mlの0.1N HCl(溶解媒体)を溶解容器に注ぎ、37℃まで加熱した。
ii.温度が37℃に達すると、各製剤の溶液1mlを溶解容器に添加した。
iii.混合物を、パドルで、50rpmの速度で、30分間にわたって撹拌した。
iv.約3mlの混合物を取り、試料キュベットの中に添加し、次に、形成されたマイクロエマルジョンの粒径を、製造者より提供されたマニュアルに記載された指示に従って、動的光散乱検出器(Zetasizer3000,Malvern Inst.,英国)で測定した。
表1
0.1N HCl溶液(人工胃液)中の実施例3から実施例8の製剤によって形成されたマイクロエマルジョンの粒径を、次の手順で測定した。
生物学的利用能試験は、3人の健康な若い男性志願者において、F(I)−1(硬カプセル剤)、F(I)−1(軟カプセル剤)、F(V)−3を含有するシクロスポリン薬物のそれぞれについて実施した。一晩の絶食後、試験製剤の1回分の服用量を志願者に投与し、被検者の血液試料を、服用前(0時間後)、ならびに服用の0.5時間後、1時間後、1.33時間後、1.67時間後、2時間後、2.5時間後、3時間後、4時間後、6時間後、9時間後、12時間後、および24時間後に採取した。シクロスポリンの血漿濃度を、高速液体クロマトグラフィーおよび質量分析法(LC−Mass)によって測定した。
米国特許第6,436,430B1号明細書
米国特許第6,312,704B1号明細書
米国特許第6,057,289号明細書
米国特許第5,965,160号明細書
米国特許第5,993,858号明細書
米国特許第6,054,136号明細書
米国特許第6,458,373B1号明細書
米国特許第6,596,306B1号明細書
米国特許第6,638,522B1号明細書
米国特許第7,094,804B2号明細書
米国特許第6,960,563B2号明細書
Claims (6)
- シクロスポリンを含む薬物の経口用自己乳化医薬組成物であって、
(a)治療上有効量のシクロスポリン、
(b)ポリソルベート、およびオレオイルポリオキシルグリセリドを含む界面活性剤、ならびに、
(c)エタノール、イソプロパノール、ポリエチレングリコール(PEG)、グリセリン、プロピレングリコール、およびそれらの混合物からなる群から選択される1つ以上の親水性担体を含み、
前記組成物のHLB値は8〜15の範囲にあるが、ただし、前記組成物は油相を含有しない、経口用自己乳化医薬組成物。 - 前記親水性担体は、エタノールである、請求項1に記載の経口用自己乳化医薬組成物。
- 前記組成物は、水系溶液に接触すると、800nm未満の粒径のエマルジョン/マイクロエマルジョンを形成する、請求項1に記載の経口用自己乳化医薬組成物。
- 前記薬物は、前記組成物の0.1重量%〜50重量%の量で存在する、請求項1に記載の経口用自己乳化医薬組成物。
- 前記親水性担体は、前記組成物の1重量%〜30重量%の量で存在する、請求項1に記載の経口用自己乳化医薬組成物。
- 前記界面活性剤は、前記組成物の10重量%〜90重量%の量で存在する、請求項1に記載の経口用自己乳化医薬組成物。
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US11/944,239 US20090130198A1 (en) | 2007-11-21 | 2007-11-21 | Pharmaceutical composition with enhanced bioavailability |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017204210A1 (ja) | 2016-05-24 | 2017-11-30 | 三生医薬株式会社 | 経口医薬組成物及び該組成物からなる粒子状製剤の製造方法 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0922806B8 (pt) * | 2008-12-03 | 2021-05-25 | Astellas Deutschland Gmbh | composição farmacêutica oral compreendendo bendamustina |
PT2519261E (pt) | 2009-12-28 | 2014-02-12 | Reig Jofre S A Lab | Composição farmacêutica líquida oral de nifedipina |
KR101752944B1 (ko) | 2010-05-03 | 2017-07-03 | 테이코쿠 팔마 유에스에이, 인코포레이티드 | 비수성의 탁산 프로에멀젼 제제, 및 그의 제조 및 사용 방법 |
MY158809A (en) * | 2010-09-22 | 2016-11-15 | Craun Res Sdn Bhd | Pharmaceutical compositions for calanolides, their derivatives and analogues, and process for producing the same |
CN102389401B (zh) * | 2011-11-22 | 2013-05-22 | 陆荣政 | 一种右旋布洛芬颗粒及其制备方法 |
KR101211902B1 (ko) * | 2012-04-30 | 2012-12-13 | 주식회사 휴온스 | 사이클로스포린 함유 무자극성 나노에멀젼 안약 조성물 |
JO3685B1 (ar) | 2012-10-01 | 2020-08-27 | Teikoku Pharma Usa Inc | صيغ التشتيت الجسيمي للتاكسين غير المائي وطرق استخدامها |
CN105491886B (zh) | 2013-08-27 | 2019-01-29 | V·沃道里斯 | 苯达莫司汀医药组合物 |
RU2746548C2 (ru) * | 2014-11-04 | 2021-04-15 | Иннофармакс, Инк. | Пероральное введение неустойчивых или плохо всасывающихся лекарственных средств |
MX2018001989A (es) * | 2015-08-19 | 2018-06-19 | Vivus Inc | Formulaciones farmaceuticas. |
JP2020152674A (ja) * | 2019-03-20 | 2020-09-24 | 株式会社リコー | 難水溶性化合物の可溶化物の製造方法 |
EP3998063A4 (en) * | 2019-07-08 | 2023-03-15 | MORESCO Corporation | COMPOSITIONS FOR PREPARING MICROEMULSION, MICROEMULSION, METHOD FOR PRODUCING COMPOSITION AND MICROEMULSION, AND USE OF MICROEMULSION |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8630273D0 (en) * | 1986-12-18 | 1987-01-28 | Til Medical Ltd | Pharmaceutical delivery systems |
IL102003A0 (en) * | 1991-06-03 | 1992-12-30 | Merck Sharp & Dohme | Pharmaceutical formulation of a benzodiazepine |
US6054136A (en) * | 1993-09-30 | 2000-04-25 | Gattefosse S.A. | Orally administrable composition capable of providing enhanced bioavailability when ingested |
US6312704B1 (en) * | 1993-09-30 | 2001-11-06 | Gattefosse, S.A. | Orally administrable composition capable of providing enhanced bioavailability when ingested |
JPH11504028A (ja) * | 1995-04-24 | 1999-04-06 | イースム リサーチ ディベロップメント カンパニー オブ ザ ヒーブル ユニバーシティ オブ エルサレム | 油/水エマルジョンを作り出す自己乳化性配合物 |
ATE263550T1 (de) * | 1995-08-25 | 2004-04-15 | Sangstat Medical Corp | Orale cyclosporinformulierungen |
KR970064620A (ko) * | 1996-03-05 | 1997-10-13 | 임성기 | 사이클로스포린-함유 외용약제 조성물 |
US5993858A (en) * | 1996-06-14 | 1999-11-30 | Port Systems L.L.C. | Method and formulation for increasing the bioavailability of poorly water-soluble drugs |
US6458373B1 (en) * | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
CA2278675A1 (en) * | 1997-01-30 | 1998-08-06 | Novartis Ag | Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil |
CZ301382B6 (cs) * | 1997-03-12 | 2010-02-10 | Abbott Laboratories Chad377/Ap6D-2 | Hydrofilní binární systémy pro podávání cyklosporinu |
ID25908A (id) * | 1998-03-06 | 2000-11-09 | Novartis Ag | Prakonsentrat-prakonsentrat emulsi yang mengandung siklosporin atau makrolida |
AU3843999A (en) * | 1998-05-07 | 1999-11-23 | Elan Corporation, Plc | Solvent/cosolvent free microemulsion and emulsion preconcentrate drug delivery systems |
DK0982035T3 (da) * | 1998-08-18 | 2004-06-28 | Panacea Biotec Ltd | Cyclosporinpræparater |
RU2257917C2 (ru) * | 1998-12-11 | 2005-08-10 | Фармасолюшнз, Инк. | Самоэмульгирующиеся композиции для плохорастворимых в воде лекарственных препаратов |
US6294192B1 (en) * | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6057289A (en) * | 1999-04-30 | 2000-05-02 | Pharmasolutions, Inc. | Pharmaceutical composition comprising cyclosporin in association with a carrier in a self-emulsifying drug delivery system |
US6596306B1 (en) * | 2000-07-07 | 2003-07-22 | David Ho Sue San Ho | Drug delivery system:formulation for fat-soluble drugs |
DE10133305B4 (de) * | 2001-07-12 | 2004-06-03 | Aquanova German Solubilisate Technologies (Agt) Gmbh | Ubichinon Konzentrat |
US6960563B2 (en) * | 2001-08-31 | 2005-11-01 | Morton Grove Pharmaceuticals, Inc. | Spontaneous emulsions containing cyclosporine |
JP2005343799A (ja) * | 2004-05-31 | 2005-12-15 | Nisshin Oillio Group Ltd | 水分散性植物ステロース製剤と油脂含有水分散性植物ステロール製剤 |
KR100678829B1 (ko) * | 2004-12-06 | 2007-02-05 | 한미약품 주식회사 | 타크로리무스의 경구용 마이크로에멀젼 조성물 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017204210A1 (ja) | 2016-05-24 | 2017-11-30 | 三生医薬株式会社 | 経口医薬組成物及び該組成物からなる粒子状製剤の製造方法 |
EP4279137A2 (en) | 2016-05-24 | 2023-11-22 | Sunsho Pharmaceutical Co., Ltd. | Oral pharmaceutical composition and method for producing particulate formulation comprising composition |
Also Published As
Publication number | Publication date |
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EP2062571A1 (en) | 2009-05-27 |
JP2016106152A (ja) | 2016-06-16 |
EP2062571B8 (en) | 2012-12-19 |
ES2396723T3 (es) | 2013-02-25 |
CN101439015A (zh) | 2009-05-27 |
EP2062571B1 (en) | 2012-11-14 |
JP2009132712A (ja) | 2009-06-18 |
US20090130198A1 (en) | 2009-05-21 |
CN101439015B (zh) | 2013-02-13 |
JP2014098039A (ja) | 2014-05-29 |
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|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |