JP4536373B2 - 新規組成物 - Google Patents
新規組成物 Download PDFInfo
- Publication number
- JP4536373B2 JP4536373B2 JP2003504977A JP2003504977A JP4536373B2 JP 4536373 B2 JP4536373 B2 JP 4536373B2 JP 2003504977 A JP2003504977 A JP 2003504977A JP 2003504977 A JP2003504977 A JP 2003504977A JP 4536373 B2 JP4536373 B2 JP 4536373B2
- Authority
- JP
- Japan
- Prior art keywords
- spironolactone
- nanosuspension
- nanoparticles
- drug
- stabilizer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
表1は、本発明に係るスピロノラクトンの代表的な調製物を例示するものである。
安定化剤の水溶液の調製物を、注射用の水または緩衝液中に添加し、透明な溶液が得られるまで磁気撹拌した。適当な量の表面活性剤水溶液でスピロノラクトンを湿らせ、スラリーを形成した。得られた懸濁液を高度の剪断分散装置を用いて分散化した。懸濁液は発泡形成を避けるため、磁気撹拌し続けた。得られた懸濁液を高圧ピストンギャップホモジナイザーに通し、ナノ懸濁液を得た。製剤1〜7はAvestin C5(商標)を用いて調製し、製剤8および9はAvestin C50(商標)を用いて調製した。均質化の際、薬剤粒子はキャビテーション効果および剪断力によって分散し、小さな微粒子およびナノ粒子を形成する。粒子サイズはZetasizer 3000 HS(商標) (Malvern)を用いて、光子相関分光法(PCS)によって決定した。D50およびD90は、Coulter LS230を用いてレーザー回折によって測定した。
本発明に係るスピロノラクトンのナノ懸濁液は、製剤が提供する種々の飽和濃度の効果を調べるために、Caco-2単層細胞を通した薬剤送達に対する効果を検討した。
ナノ懸濁液は、pH 6.5に調整した種々の量の25mM MES添加ハンクス液(HBSS)で希釈し、平衡になるまで震盪した。基準溶液として、対応する濃度の表面活性剤の存在下で、HBSS/MES溶液中で飽和濃度に達するまで各薬剤の過剰量の粗粉末を震盪した。沈殿からの溶液の分離は、4500 refで15分間の遠心によって行なった。
Caco-2細胞(継代33-41)を24 mmポリカーボネートフィルターメンブレン(ポアサイズ0.4μm;Transwell, Corning, MA)上で、21〜27日間培養した。試験溶液2.5mlを頂部、緩衝液2.5mlを基底外側に添加した。レシーバーチェンバーからの試料を0, 30, 60, 90, 120分に採取し、その体積の新しい培地を補充した。試料は液体シンチレーション計数によって放射標識したマーカー分子、HPLCによってスピロノラクトンの分析をした。完全性のマーカーとして14C-マンニトールおよび3H-メトプロロールを使用した。さらに各実験の最初と最後にTEER(経上皮電気抵抗)測定を行なった。薬剤の流れは、時間に対する、単層を通して送達された薬剤の量の勾配から、計算した。
図1は腸膜を通したスピロノラクトンの定常状態の流れを示す。1:100, 1:30および1:10で、粗懸濁液と比較して、希釈したナノ懸濁液をドナー溶液とした方が流れの値は高かった。
ラットへの経口投与後、図2に示すように、本発明に係るスピロノラクトンナノ懸濁液を用いると、対応する粗懸濁液よりも、薬剤代謝物の血漿レベルが有意に高かった。
イヌにおけるスピロノラクトンのインビボバイオアベイラビリティは、4群のクロスオーバー(食後/絶食)試験で行なった。上述のような粗懸濁液(基準)またはナノ懸濁液(被験)を8匹のオスのビーグル犬に5mg/kgの用量で投与した。ウォッシュアウト期間は10日だった。LC/MS/MS:スピロノラクトン、カンレノン、TMSL、およびHTMSL、(LOQ=0.5ng/mL)。結果は表2および表3ならびに図3および図4に示す。
Claims (4)
- スピロノラクトンのナノ粒子を含むナノ懸濁液であって、
該ナノ粒子は、光子相関分光法によって測定した平均直径が300nmから900nmの範囲であり、
該ナノ懸濁液は安定化剤を含み、該安定化剤がドキュセートナトリウムである、ナノ懸濁液。 - 前記ナノ粒子は、光子相関分光法によって測定した平均直径が400nmから600nmの範囲である、請求項1記載のナノ懸濁液。
- 水性ナノ懸濁液である、請求項1または2記載のナノ懸濁液。
- 請求項1〜3のいずれかに記載のナノ懸濁液を含む薬学的製剤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0114532.5A GB0114532D0 (en) | 2001-06-14 | 2001-06-14 | Novel compositions |
PCT/IB2002/003136 WO2002102391A2 (en) | 2001-06-14 | 2002-06-14 | Composition comprising nanoparticulate spironolactone |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2004534074A JP2004534074A (ja) | 2004-11-11 |
JP2004534074A5 JP2004534074A5 (ja) | 2006-01-05 |
JP4536373B2 true JP4536373B2 (ja) | 2010-09-01 |
Family
ID=9916594
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003504977A Expired - Fee Related JP4536373B2 (ja) | 2001-06-14 | 2002-06-14 | 新規組成物 |
Country Status (6)
Country | Link |
---|---|
US (2) | US20040151776A1 (ja) |
EP (1) | EP1429781A2 (ja) |
JP (1) | JP4536373B2 (ja) |
AU (1) | AU2002347094A1 (ja) |
GB (1) | GB0114532D0 (ja) |
WO (1) | WO2002102391A2 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0127832D0 (en) * | 2001-11-20 | 2002-01-09 | Jagotec Ag | Method for the preparation of pharmaceutical nanosuspensions |
CN100553625C (zh) | 2002-04-09 | 2009-10-28 | 弗拉梅技术公司 | 活性成分微囊的口服混悬液 |
JP2006511525A (ja) * | 2002-12-13 | 2006-04-06 | ヤゴテック アーゲー | ナノ粒子状スピロノラクトン局所製剤 |
JP2006089386A (ja) * | 2004-09-21 | 2006-04-06 | Nippon Tenganyaku Kenkyusho:Kk | ステロイドまたはステロイド誘導体を含有する懸濁性医薬組成物 |
US9023400B2 (en) * | 2006-05-24 | 2015-05-05 | Flamel Technologies | Prolonged-release multimicroparticulate oral pharmaceutical form |
US7897691B2 (en) | 2008-05-09 | 2011-03-01 | Gm Global Technology Operations, Inc. | Proton exchange membranes for fuel cell applications |
JP5185039B2 (ja) * | 2008-09-24 | 2013-04-17 | 富士フイルム株式会社 | 光学フィルム、その製造方法、並びにそれを用いた偏光板及び液晶表示装置 |
US10493083B2 (en) | 2015-10-30 | 2019-12-03 | Cmp Development Llc | Spironolactone aqueous compositions |
EP3368045A4 (en) | 2015-10-30 | 2019-08-07 | CMP Development LLC | AQUEOUS SPIRONOLACTONE COMPOSITIONS |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4011316A (en) * | 1975-02-24 | 1977-03-08 | Research Institute For Medicine And Chemistry Inc. | Cyclohexa-2,5-diene-1-thiones |
IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
DE3623376A1 (de) * | 1986-07-11 | 1988-01-21 | Behringwerke Ag | Pharmazeutische formulierung und verfahren zu deren herstellung |
US4837211A (en) * | 1987-04-06 | 1989-06-06 | Carolina Medical Products, Inc. | Spironolactone composition |
US5091188A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5567592A (en) * | 1994-02-02 | 1996-10-22 | Regents Of The University Of California | Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal |
GB9409778D0 (en) * | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
DE4440337A1 (de) * | 1994-11-11 | 1996-05-15 | Dds Drug Delivery Services Ges | Pharmazeutische Nanosuspensionen zur Arzneistoffapplikation als Systeme mit erhöhter Sättigungslöslichkeit und Lösungsgeschwindigkeit |
FR2730231B1 (fr) * | 1995-02-02 | 1997-04-04 | Fournier Sca Lab | Association de fenofibrate et de vitamine e, utilisation en therapeutique |
AU4777896A (en) * | 1995-02-10 | 1996-08-27 | G.D. Searle & Co. | Use of low dose amount of spironolactone for treatment of cardiovascular disease |
US5510118A (en) * | 1995-02-14 | 1996-04-23 | Nanosystems Llc | Process for preparing therapeutic compositions containing nanoparticles |
EP0810853B1 (en) * | 1995-02-24 | 2004-08-25 | Elan Pharma International Limited | Aerosols containing nanoparticle dispersions |
US5716928A (en) * | 1995-06-07 | 1998-02-10 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5891469A (en) * | 1997-04-02 | 1999-04-06 | Pharmos Corporation | Solid Coprecipitates for enhanced bioavailability of lipophilic substances |
US5891845A (en) * | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
UA74141C2 (uk) * | 1998-12-09 | 2005-11-15 | Дж.Д. Сірл Енд Ко. | Фармацевтична композиція на основі тонкоподрібненого еплеренону (варіанти), спосіб її одержання та спосіб лікування розладів, опосередкованих альдостероном (варіанти) |
US6180138B1 (en) * | 1999-01-29 | 2001-01-30 | Abbott Laboratories | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption |
US6294192B1 (en) * | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6267985B1 (en) * | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
DE60019741T2 (de) * | 1999-12-08 | 2006-03-02 | Pharmacia Corp., Chicago | Nanopartikelzusammensetzungen enthaltend eplerenon |
AU2001284772A1 (en) * | 2000-08-10 | 2002-02-25 | Delsys Pharmaceutical Corporation | Improved solid pharmaceutical dosage formulation of hydrophobic drugs |
-
2001
- 2001-06-14 GB GBGB0114532.5A patent/GB0114532D0/en not_active Ceased
-
2002
- 2002-06-14 EP EP02751549A patent/EP1429781A2/en not_active Withdrawn
- 2002-06-14 AU AU2002347094A patent/AU2002347094A1/en not_active Abandoned
- 2002-06-14 JP JP2003504977A patent/JP4536373B2/ja not_active Expired - Fee Related
- 2002-06-14 WO PCT/IB2002/003136 patent/WO2002102391A2/en active Application Filing
- 2002-06-14 US US10/480,573 patent/US20040151776A1/en not_active Abandoned
-
2007
- 2007-07-25 US US11/881,337 patent/US20080069886A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JP2004534074A (ja) | 2004-11-11 |
EP1429781A2 (en) | 2004-06-23 |
US20080069886A1 (en) | 2008-03-20 |
US20040151776A1 (en) | 2004-08-05 |
WO2002102391A2 (en) | 2002-12-27 |
GB0114532D0 (en) | 2001-08-08 |
AU2002347094A1 (en) | 2003-01-02 |
WO2002102391A3 (en) | 2004-04-29 |
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