JP4792457B2 - 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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- JP4792457B2 JP4792457B2 JP2007504268A JP2007504268A JP4792457B2 JP 4792457 B2 JP4792457 B2 JP 4792457B2 JP 2007504268 A JP2007504268 A JP 2007504268A JP 2007504268 A JP2007504268 A JP 2007504268A JP 4792457 B2 JP4792457 B2 JP 4792457B2
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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 description 152
- 102000004877 Insulin Human genes 0.000 title claims description 76
- 108090001061 Insulin Proteins 0.000 title claims description 76
- 229940125396 insulin Drugs 0.000 title claims description 76
- 239000011859 microparticle Substances 0.000 title claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 238000001694 spray drying Methods 0.000 claims description 19
- 239000002245 particle Substances 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 1
- 150000004676 glycans Chemical class 0.000 claims 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 4
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- 240000006365 Vitis vinifera Species 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
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- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
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- 229920001184 polypeptide Polymers 0.000 description 3
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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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
-
- 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
-
- 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
-
- 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
-
- 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
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 (7)
- 室温で安定であるインスリンのマイクロ粒子であって、
当該マイクロ粒子は:
インスリンの等電点(5.4)未満のpHを有するインスリンの水溶液であって、該水溶液のインスリン濃度が5〜100mg/mLのものを噴霧乾燥して得たものであり;
前記粒子の90%以上が9μm未満の体積径を示し;
該マイクロ粒子の80%が、5μm未満の空気動力学的直径を有し;且つ
10重量%未満の塩を含有し、
噴霧乾燥される前記のインスリンの水溶液は、酢酸の非緩衝性水溶液の形態で調製されることを特徴とするマイクロ粒子。 - 0.2g/cm3未満のタップ密度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。
- 単糖類、多糖類、アミノ酸、リン脂質及びポリアルコールからなる群から選択される賦形剤をさらに含む、請求項1又は2に記載のマイクロ粒子。
- 前記賦形剤は、マンニトールであることを特徴とする請求項3に記載のマイクロ粒子。
- 不定形のインスリンを含有することを特徴とする請求項1乃至4のいずれか一項に記載のマイクロ粒子。
- 請求項1乃至5のいずれか一項に記載のマイクロ粒子を含有する、吸入されるのに適した薬学的組成物。
- 請求項1乃至5のいずれか一項に記載のマイクロ粒子からなる、請求項6に記載の薬学的組成物。
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PCT/EP2004/050371 WO2005092301A1 (en) | 2004-03-26 | 2004-03-26 | Insulin highly respirable microparticles |
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WO2005092301A1 (en) | 2005-10-06 |
US7625865B2 (en) | 2009-12-01 |
EP1734938B1 (en) | 2012-06-20 |
JP2007530465A (ja) | 2007-11-01 |
US20070154404A1 (en) | 2007-07-05 |
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