JP2007530465A - 高度に呼吸に適したインスリンのマイクロ粒子 - Google Patents
高度に呼吸に適したインスリンのマイクロ粒子 Download PDFInfo
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- JP2007530465A JP2007530465A JP2007504268A JP2007504268A JP2007530465A JP 2007530465 A JP2007530465 A JP 2007530465A JP 2007504268 A JP2007504268 A JP 2007504268A JP 2007504268 A JP2007504268 A JP 2007504268A JP 2007530465 A JP2007530465 A JP 2007530465A
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 194
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Images
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Otolaryngology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
全ての処方の活性は、HPLCにより、算出した。非特許文献11によると、異なる条件で行ったHPLCでは、効能(potency)(USP26では、効能は、「ASSAY」において述べる特定の標準的な試験と比較して、評価される。)、純度(「関連するタンパク質」の量)及び共有性凝集(いわゆる、インスリンよりも大きな分子量を有する不純物)の存在に関する情報を提供する。なお、純度及び共有性凝集については、非特許文献10に開示の通りである。
A)処方
高度の精製したウシ由来のインスリン2550mgを、10−2Mの塩酸水溶液200mLに溶解した。この溶液に、攪拌しながら、100mLの蒸留水を添加し、その後、450mgのマンニトールを添加して、最終濃度が10mg/mLのインスリン溶液(1mL当たり8.5mgのウシインスリン)とした。この澄明な溶液のpHを、0.1NのNaOHを滴下して、4.35に調節した。
上述の溶液をろ過し、以下の条件で、Mini Spray Drier Buchi、model 191(Buchi Labortechnik AG社製、Flawil、スイス)装置を用いて、噴霧乾燥した:供給流率 195mL/時間;ノズルガス流率 600nL/時間;噴霧ノズル径 1.0mm;入口の空気温度 120℃;製造に係る出口の温度 42℃;吸引能力 100%に設定。収率は、約60%であった。
収集した粉末に関する共有性凝集物及び分解産物(A21デスアミドインスリン)について、非特許文献10(p.1368〜1381)に従って、形態の検討には走査型電子顕微鏡(SEM)を、粒子径分布にはレーザー回折を、呼吸適用画分の検討にはAndersen Cascade Impactorを、それぞれ用いて、検討した。
A)処方
ウシ由来のインスリン975mgを、95mLの水性希酢酸(pH2.6)に溶解した。この溶液に、1MのNaOH0.6mLを添加した。この澄明な溶液のpHは、3.27であった。
上述の溶液をろ過し、以下の条件で、Mini Spray Drier Buchi、model 191(Buchi Labortechnik AG社製、Flawil、スイス)装置を用いて、噴霧乾燥した:供給流率 200mL/時間;ノズルガス流率 500nL/時間;噴霧ノズル径 1.0mm;入口の空気温度 130℃;製造に係る出口の温度 55℃;吸引能力 100%に設定。収率は、約50%であった。
収集した粉末に関する共有性凝集物及び分解産物(A21デスアミドインスリン)について、非特許文献10及び上述のアッセイに従って、検討した。上述の効能は、28.9UI/mgであり、上述の関連タンパクは、0.6%であり、インスリンよりも大きな分子量を有する不純物は、0.33%であった。この粉末の粒子径分布は、体積径(volume diameter)として、4.06(d10)、4.36(d50)及び4.93(d90)であった。Andersen Cascade Impactorから得た呼吸適用性(5μm未満のもの)は、83.9%であった。梱包性の指標であるタップ密度(非特許文献10)は、0.1g/cm3であった。脱気した蒸留水に溶解した粉末のpHは、6.4であった。得たマイクロ粒子は、干しブドウ型の形状を呈した(図1)。
A)処方
高度の精製したウシ由来のインスリン1750mgを、10−2Mの塩酸水溶液120mLに溶解した。この溶液に、1NのNaOHを0.7mL滴下して、pHを4.44に調節した。この溶液は、澄明であって、1mL当たり約15mgの固形物を含有する。
上述の溶液をろ過し、以下の条件で、Mini Spray Drier Buchi、model 191(Buchi Labortechnik AG社製、Flawil、スイス)装置を用いて、噴霧乾燥した:供給流率 195mL/時間;ノズルガス流率 600nL/時間;噴霧ノズル径 1.0mm;入口の空気温度 120℃;製造に係る出口の温度 46℃;吸引能力 100%に設定。収率は、約55%であった。
収集した粉末に関する共有性凝集物及び分解産物(A21デスアミドインスリン)について、非特許文献10に従って、形態の検討には走査型電子顕微鏡(SEM)を、粒子径分布にはレーザー回折を、呼吸適用画分の検討にはAndersen Cascade Impactorを、それぞれ用いて、検討した。
Claims (16)
- インスリンの等電点未満のpHを有する澄明なインスリン溶液を噴霧乾燥して得た、インスリンの吸入用粉末であって、マイクロ粒子の90%は、体積径として9μm未満の粒子径を有することを特徴とする、インスリンの吸入用粉末。
- タップ密度として計測した梱包特性は、0.2g/cm3未満であることを特徴とする請求項1に記載のインスリンの吸入用粉末。
- インスリンの等電点未満のpHを有する澄明なインスリン溶液を噴霧乾燥して得た、インスリンの吸入用粉末であって、波形又は干しブドウ型の粒子形を呈するマイクロ粒子を有することを特徴とする、インスリンの吸入用粉末。
- インスリンの等電点未満のpHを有する澄明なインスリン溶液を噴霧乾燥して得た、インスリンの吸入用粉末であって、空気動力学的直径として5μm未満の画分として測定した呼吸適用性画分は、80%以上であることを特徴とする、インスリンの吸入用粉末。
- インスリンと賦形剤とを有し、インスリンの等電点未満のpHを有する澄明な溶液を、乾燥噴霧して得たものであることを特徴とする請求項1に記載のマイクロ粒子。
- 当該マイクロ粒子を得る前記のインスリン溶液は、好ましく5.4未満のpHを有することを特徴とする請求項1に記載のマイクロ粒子。
- 好適な賦形剤は、単糖類、多糖類、アミノ酸、リン脂質及びポリアルコールであって、より好ましい賦形剤は、マンニトールであることを特徴とする請求項1に記載のマイクロ粒子。
- インスリンの溶解に使用する酸は、0.01Nの塩酸などの鉱酸であることを特徴とする請求項1に記載のマイクロ粒子。
- 治療用薬物の澄明な酸性溶液を噴霧乾燥して得られるマイクロ粒子であって、前記薬物の溶解に使用する揮発性有機酸は、噴霧乾燥中、部分的に揮発し、蒸留水に溶解した際、元の値よりも大きなpHを有する溶液を与える粒子を残存させることを特徴とするマイクロ粒子。
- インスリンの溶解に使用する酸は、揮発性有機酸であることを特徴とする請求項1に記載のマイクロ粒子。
- インスリンの溶解に使用する酸は、希酢酸などの揮発性有機酸であることを特徴とする請求項1に記載のマイクロ粒子。
- インスリンと、インスリンの溶解に使用する酸から形成された塩とから実質的になることを特徴とする請求項1に記載のマイクロ粒子。
- 当該マイクロ粒子は、全固形物の重量に対して、10%未満の塩を含有することを特徴とする請求項1に記載のマイクロ粒子。
- 前記インスリンは、不定形であることを特徴とする請求項1に記載のマイクロ粒子。
- 肺への投与を介して治療適用を可能とする呼吸適用範囲の粒子径を有することを特徴とする請求項1乃至14のいずれか一項に記載のマイクロ粒子。
- 噴霧乾燥されるべき前記溶液は、1mL当たり5〜100mgのインスリンを含有することを特徴とする請求項1に記載の方法。
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Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1196430E (pt) | 1999-06-29 | 2012-04-18 | Mannkind Corp | Purificação e estabilização de péptidos e proteínas em agentes farmacêuticos |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
WO2003080149A2 (en) | 2002-03-20 | 2003-10-02 | Mannkind Corporation | Inhalation apparatus |
DE602005024413D1 (de) | 2004-08-20 | 2010-12-09 | Mannkind Corp | Katalyse der diketopiperazinsynthese |
ES2540886T3 (es) | 2004-08-23 | 2015-07-14 | Mannkind Corporation | Sales de dicetopiperazina para la administración de fármacos |
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AU2007216966C1 (en) | 2006-02-22 | 2014-03-20 | Mannkind Corporation | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent |
EP2076242B8 (en) * | 2006-07-27 | 2013-02-20 | Nektar Therapeutics | Aerosolizable formulation comprising insulin for pulmonary delivery |
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TWI532497B (zh) * | 2008-08-11 | 2016-05-11 | 曼凱公司 | 超快起作用胰島素之用途 |
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WO2011049776A1 (en) * | 2009-10-22 | 2011-04-28 | Cpex Pharmaceuticals, Inc. | Therapeutically effective preparations of insulin |
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EP2694402B1 (en) | 2011-04-01 | 2017-03-22 | MannKind Corporation | Blister package for pharmaceutical cartridges |
US9060938B2 (en) | 2011-05-10 | 2015-06-23 | Bend Research, Inc. | Pharmaceutical compositions of active agents and cationic dextran polymer derivatives |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
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MX2020009878A (es) | 2013-07-18 | 2022-07-27 | Mannkind Corp | Composiciones farmaceuticas en polvo seco estables al calor y metodos. |
JP2016530930A (ja) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | 通気装置及び方法 |
WO2015052088A1 (en) | 2013-10-07 | 2015-04-16 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
US10307464B2 (en) | 2014-03-28 | 2019-06-04 | Mannkind Corporation | Use of ultrarapid acting insulin |
WO2016007682A1 (en) | 2014-07-08 | 2016-01-14 | Amphastar Pharmaceuticals Inc. | Micronized insulin, micronized insulin analogues, and methods of manufacturing the same |
US10556000B2 (en) * | 2014-07-18 | 2020-02-11 | Msd Wellcome Trust Hilleman Laboratories Pvt. Ltd. | Thermostable spray dried rotavirus vaccine formulation and process thereof |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
US10322168B2 (en) | 2016-01-07 | 2019-06-18 | Amphastar Pharmaceuticals, Inc. | High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same |
MX2019006463A (es) | 2016-12-16 | 2019-08-14 | Novo Nordisk As | Composiciones farmaceuticas que contienen insulina. |
JP7496826B2 (ja) | 2018-09-10 | 2024-06-07 | ラング セラピューティクス,エルエルシー | Cav-1タンパク質の修飾ペプチドフラグメント及び線維症の治療におけるその使用 |
EP3849581A4 (en) * | 2018-09-10 | 2022-07-06 | Board of Regents, The University of Texas System | DRY POWDER FORMULATION OF CAVEOLIN-1 PEPTIDES AND METHODS OF USING THE SAME |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001093837A2 (en) * | 2000-06-08 | 2001-12-13 | Eli Lilly And Company | Protein powder for pulmonary delivery |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1479283A (en) * | 1973-07-23 | 1977-07-13 | Bespak Industries Ltd | Inhaler for powdered medicament |
IT1116047B (it) * | 1979-04-27 | 1986-02-10 | Sigma Tau Ind Farmaceuti | Dispositivo per la rapida inalazione di farmaci in polvere da parte di persone sofferenti di asma |
NZ222907A (en) | 1986-12-16 | 1990-08-28 | Novo Industri As | Preparation for intranasal administration containing a phospholipid absorption enhancing system |
DK479189D0 (da) | 1989-01-06 | 1989-09-28 | Hans Gernot Schenk | Inhalator |
GB8904370D0 (en) | 1989-02-25 | 1989-04-12 | Cosmas Damian Ltd | Liquid delivery compositions |
GB8918879D0 (en) | 1989-08-18 | 1989-09-27 | Danbiosyst Uk | Pharmaceutical compositions |
IT1243344B (it) | 1990-07-16 | 1994-06-10 | Promo Pack Sa | Inalatore plurimonodose per medicamenti in polvere |
YU48420B (sh) | 1991-03-25 | 1998-07-10 | Hoechst Aktiengesellschaft | Postupak za dobijanje biološki razgradljivih mikročestica sa dugotrajnim delovanjem |
AU659645B2 (en) | 1991-06-26 | 1995-05-25 | Inhale Therapeutic Systems | Storage of materials |
GB9116610D0 (en) | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
US5320094A (en) * | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
EP0655237A1 (de) | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medizinische Aerosolformulierung |
PL179443B1 (pl) | 1994-03-07 | 2000-09-29 | Inhale Therapeutic Syst | Kompozycja insuliny, sposób wytwarzania kompozycji insuliny i sposób wytwarzania dawki insuliny w postaci aerozolu PL PL PL PL |
US20020052310A1 (en) * | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
WO1999055362A1 (en) | 1998-04-29 | 1999-11-04 | Genentech, Inc. | Spray dried formulations of igf-i |
ATE238768T1 (de) | 1998-06-24 | 2003-05-15 | Advanced Inhalation Res Inc | Grosse poröse partikel ausgestossen von einem inhalator |
GB9814172D0 (en) | 1998-06-30 | 1998-08-26 | Andaris Ltd | Formulation for inhalation |
GB0009468D0 (en) * | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formulations for use in inhaler devices |
JP2005504715A (ja) * | 2000-12-29 | 2005-02-17 | アドバンスト インハレーション リサーチ,インコーポレイテッド | 持続放出特性を有する吸入用粒子 |
-
2004
- 2004-03-26 JP JP2007504268A patent/JP4792457B2/ja not_active Expired - Lifetime
- 2004-03-26 WO PCT/EP2004/050371 patent/WO2005092301A1/en active Application Filing
- 2004-03-26 US US10/593,861 patent/US7625865B2/en active Active
- 2004-03-26 EP EP04723612A patent/EP1734938B1/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001093837A2 (en) * | 2000-06-08 | 2001-12-13 | Eli Lilly And Company | Protein powder for pulmonary delivery |
Non-Patent Citations (1)
Title |
---|
JPN6010015321, Quaglia,F. et al., "Feeding liquid, non−ionic surfactant and cyclodextrin affect the properties of insulin−loaded poly(l", J. Control. Release, 20030117, Vol.86,No.2−3, P.267−278 * |
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US7625865B2 (en) | 2009-12-01 |
WO2005092301A1 (en) | 2005-10-06 |
EP1734938B1 (en) | 2012-06-20 |
EP1734938A1 (en) | 2006-12-27 |
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