JP2010533707A - 11−デオキシ−プロスタグランジン化合物を含む医薬組成物およびその安定化方法 - Google Patents
11−デオキシ−プロスタグランジン化合物を含む医薬組成物およびその安定化方法 Download PDFInfo
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- JP2010533707A JP2010533707A JP2010516705A JP2010516705A JP2010533707A JP 2010533707 A JP2010533707 A JP 2010533707A JP 2010516705 A JP2010516705 A JP 2010516705A JP 2010516705 A JP2010516705 A JP 2010516705A JP 2010533707 A JP2010533707 A JP 2010533707A
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- deoxy
- prostaglandin compound
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- compound
- prostaglandin
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Classifications
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K9/4841—Filling excipients; Inactive ingredients
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
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Abstract
Description
Aは、−CH3、−CH2OH、−COCH2OH、−COOHまたはそれらの官能性誘導体;
R1は非置換またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環で置換された、二価の飽和または不飽和の低〜中級の脂肪族炭化水素(脂肪族炭化水素における少なくとも1個の炭素原子は酸素、窒素または硫黄によって置換されていてもよい);
R0は非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環または複素環オキシで置換された、飽和または不飽和の低〜中級の脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環;複素環オキシである(脂肪族炭化水素における少なくとも1個の炭素原子は酸素、窒素または硫黄によって置換されていてもよい)]。
Bは、単結合、−CH2−CH2−、−CH=CH−、−C≡C−、−CH2−CH2−CH2−、−CH=CH−CH2−、−CH2−CH=CH−、−C≡C−CH2−または−CH2−C≡C−;
Zは、
Raは、非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環または複素環オキシで置換された、飽和または不飽和の低〜中級脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基(脂肪族炭化水素における少なくとも1個の炭素原子は酸素、窒素または硫黄によって置換されていてもよい)
L、N、A、およびR1は前記定義と同一]。
R2は、単結合または低級アルキレン;
R3は、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環または複素環オキシ(脂肪族炭化水素における少なくとも1個の炭素原子は酸素、窒素または硫黄によって置換されていてもよい);
L、A、B、R1およびZは前記定義と同一]。
上式中、R1およびRaにおける「不飽和」の語は、主鎖および/または側鎖の炭素原子間の結合として、少なくとも1つまたはそれ以上の2重結合および/または3重結合を孤立、分離または連続して含むことを意味する。通常の命名法に従って、連続する2つの位置間の不飽和は若い方の位置番号を表示することにより示し、連続しない2つの位置間の不飽和は両方の位置番号を表示して示す。
「アリールオキシ」の語は、式ArO−(ここで、Arは上記のようなアリール基)で示される基を意味する。
Aの「官能性誘導体」の語は、塩(好ましくは、医薬上許容し得る塩)、エーテル、エステルおよびアミド類を含む。
−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH(CH3)−CH2−、
−CH2−CH2−CH2−CH2−O−CH2−、
−CH2−CH=CH−CH2−O−CH2−、
−CH2−C≡C−CH2−O−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH(CH3)−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH(CH3)−CH2−、
など。
化合物1:11−デオキシ−13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−PGE1
化合物の量の測定は以下の通りに行った。約0.2gの試料を正確に2mLの内部標準溶液と混合し、次いで表1に示す溶解剤と混合して5mLの試料溶液を得た。約5mgの標準品の化合物1の重量を精密に量り、アセトニトリルを加えて、正確に50mL溶液とした。この液1mLを正確に量り、正確に4mLの内部標準溶液を加え、次いで溶解剤を加えて10mLの標準溶液を得た。
高速液体クロマトグラフィー分析条件:
カラム:内径約5mm、長さ約25cmのステンレス管に5μmの高速液体クロマトグラフ用オクタデシルシリル化シリカゲルを充てん
移動相:高速液体クロマトグラフ用アセトニトリルおよび過塩素酸緩衝液混液
温度:35℃
検出器:分光蛍光検出器
化合物1:11−デオキシ−13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−PGE1を用いた。
適量の水とトウモロコシデンプン由来糖アルコール液(ゼラチンに対して60重量%)を撹拌しながら加温し、次いで100重量%のゼラチン液を加えてゼラチン溶液を得る。化合物1を中鎖脂肪酸トリグリセリド(米国局方(USP/NF)品)に溶かして、120μg/g濃度の内容液を調製する。調製したゼラチン液と内容液を軟カプセル形成充てん機に供し、上記内容液を封入後、適度な硬度となるまで乾燥させ、軟ゼラチンカプセル製品とする。
上記製剤例で製造された軟ゼラチンカプセルは40℃にて6ヶ月間または55℃にて1ヶ月間保管された。カプセル20個をとり、適当量の精製水を加えてカプセルを膨潤させた後、液体クロマトグラフ用酢酸エチル10mLを加えてカプセルを切り開き内容液を取り出した。表示量に従い、化合物100μg当り内部標準液1.0mLを正確に加えて、さらに1mL当り化合物が10μgとなるように液体クロマトグラフ用酢酸エチルを加えて、試料溶液とした。
高速液体クロマトグラフィー分析条件
カラム:内径約5mm、長さ約25cmのステンレス管に5μmの高速液体クロマトグラフ用オクタデシルシリル化シリカゲルを充てん
移動相:高速液体クロマトグラフ用アセトニトリル:高速液体クロマトグラフ用メタノール:酢酸アンモニウム混液(0.05mol/L)
温度:35℃
検出器:分光蛍光検出器
Claims (42)
- 下記式(I)
Aは、−CH3、−CH2OH、−COCH2OH、−COOHまたはそれらの官能性誘導体であり;
R1は非置換またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された、二価の飽和または不飽和の低〜中級の脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよく;
R0は非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基で置換された、飽和または不飽和の低〜中級の脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよい]
により表される11−デオキシ−プロスタグランジン化合物および脂肪酸エステルを含有する医薬組成物。 - 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−15−ケト−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−15−ケト−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14-ジヒドロ−15−ケト−16−モノまたはジフルオロ−プロスタグランジン化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16−モノまたはジハロゲン−プロスタグランジンEまたはF化合物である、請求項1記載の医薬組成物。
- プロスタグランジン化合物が11−デオキシ−13,14-ジヒドロ−15−ケト−16−モノまたはジフルオロ−プロスタグランジンEまたはF化合物である、請求項1記載の医薬組成物。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−プロスタグランジンE1化合物である、請求項1記載の医薬組成物。
- 脂肪酸エステルがグリセリドである、請求項1記載の医薬組成物。
- グリセリドが炭素原子数6〜24の脂肪酸のグリセリドである、請求項13記載の医薬組成物。
- グリセリドが炭素原子数6〜20の脂肪酸のグリセリドである、請求項13記載の医薬組成物。
- グリセリドが2以上のグリセリドの混合物である、請求項13記載の医薬組成物。
- グリセリドが脂肪酸エステル以外の油性媒体と混合されたものである、請求項13記載の医薬組成物。
- 油性媒体が鉱油である、請求項17記載の医薬組成物。
- 脂肪酸エステルがグリセリン脂肪酸エステルである、請求項1記載の医薬組成物。
- 脂肪酸エステルがプロピレングリコール脂肪酸エステルである、請求項1記載の医薬組成物。
- 脂肪酸エステルが脂肪酸と炭素原子数1〜6の一価アルコールとのエステルである、請求項1記載の医薬組成物。
- 脂肪酸エステルがパルミチン酸イソプロピルである請求項1記載の医薬組成物。
- 経口投与用製剤である、請求項1記載の医薬組成物。
- カプセル製剤である、請求項23記載の医薬組成物。
- 下記式(I)
Aは、−CH3、−CH2OH、−COCH2OH、−COOHまたはそれらの官能性誘導体であり;
R1は非置換またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された、二価の飽和または不飽和の低〜中級の脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよく;
R0は非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基で置換された、飽和または不飽和の低〜中級の脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよい]
により表される11−デオキシ−プロスタグランジン化合物の安定化方法であって、該11−デオキシ−プロスタグランジン化合物を脂肪酸エステルと混合することを含む方法。 - 可塑剤としてポリオールおよび/または糖アルコールを含有する軟ゼラチン皮膜、および該皮膜内に含まれる、下記式(I)
Aは、−CH3、−CH2OH、−COCH2OH、−COOHまたはそれらの官能性誘導体であり;
R1は非置換またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された、二価の飽和または不飽和の低〜中級の脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよく;
R0は非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基で置換された、飽和または不飽和の低〜中級の脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は随意により酸素、窒素または硫黄によって置換されていてもよい]
により表される11−デオキシ−プロスタグランジン化合物および医薬上許容し得る媒体を含む医薬組成物、を含む軟ゼラチンカプセル製剤。 - 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−15−ケト−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−15−ケト−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16−モノまたはジハロゲン−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14-ジヒドロ−15−ケト−16−モノまたはジフルオロ−プロスタグランジン化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16−モノまたはジハロゲン−プロスタグランジンEまたはF化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 11−デオキシ−プロスタグランジン化合物が11−デオキシ13,14-ジヒドロ−15−ケト−16−モノまたはジフルオロ−プロスタグランジンEまたはF化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- プロスタグランジン化合物が11−デオキシ−13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−プロスタグランジンE1化合物である、請求項26記載の軟ゼラチンカプセル製剤。
- 医薬上許容し得る媒体が脂肪酸エステルである、請求項26記載の軟ゼラチンカプセル製剤。
- 脂肪酸エステルがグリセリドである、請求項38記載の軟ゼラチンカプセル製剤。
- ポリオールがグリセリンである、請求項38記載の軟ゼラチンカプセル製剤。
- 糖アルコールがソルビトール、ソルビタン、マルチトール、トウモロコシデンプン由来糖アルコール液、還元麦芽糖水アメおよびそれらの混合物からなる群から選択される、請求項26記載の軟ゼラチンカプセル製剤。
- 糖アルコールがソルビトールおよびソルビタンを主成分とするものである請求項41記載の軟ゼラチンカプセル製剤。
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PCT/JP2008/063222 WO2009011449A2 (en) | 2007-07-19 | 2008-07-16 | Pharmaceutical composition comprising 11-deoxy-prostaglandin compound and method for stabilizing the compound |
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DK1978944T3 (da) | 2006-01-24 | 2012-11-05 | Sucampo Ag | Blød-gelatine-kapselformulering |
WO2013022079A1 (en) * | 2011-08-05 | 2013-02-14 | Sucampo Ag | Method for treating schizophrenia |
WO2014159679A1 (en) | 2013-03-12 | 2014-10-02 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for using lubiprostone to absorb fluid from the subretinal space |
US10716544B2 (en) | 2015-10-08 | 2020-07-21 | Zmk Medical Technologies Inc. | System for 3D multi-parametric ultrasound imaging |
CN108619107A (zh) * | 2018-05-28 | 2018-10-09 | 青海制药厂有限公司 | 一种含鲁比前列酮的软胶囊及其制备方法 |
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