JP4077386B2 - 医薬組成物 - Google Patents
医薬組成物 Download PDFInfo
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- JP4077386B2 JP4077386B2 JP2003337458A JP2003337458A JP4077386B2 JP 4077386 B2 JP4077386 B2 JP 4077386B2 JP 2003337458 A JP2003337458 A JP 2003337458A JP 2003337458 A JP2003337458 A JP 2003337458A JP 4077386 B2 JP4077386 B2 JP 4077386B2
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- rapamycin
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Description
a)有効成分
b)リン脂質、糖脂質、スフィンゴ脂質、ジアシルホスファチジルグリセロール、卵−ホスファチジルグリセロール、大豆−ホスファチジルグリセロール、ジアシル−ホスファチジルグリセロール、またはその塩;または飽和、モノ−またはジ−不飽和(C12−24)脂肪酸またはその塩から選択される安定化剤、および
c)有機溶媒
(ただし、有効成分と安定化剤の重量比は400:1ないし0.5:1である)
を含有する濃縮液をプラセボ脂肪エマルションに混合する段階を含む。
a)プラセボ脂肪エマルション、および
b)安定化剤であるオレイン酸ナトリウムまたはNaPOPGを含有する有効成分の有機溶媒(例えば、エタノールおよび/またはプロピレングリコールを含む)溶液
(ただし、有効成分と安定化剤の重量比は400:1〜10:1である)
を含む、有効成分[3'−デスオキシ−3−オキソ−MeBmt]1−[Val]2−シクロスポリンの静脈内投与用のエマルションを提供する。
a)有効成分および
b)安定化剤であるオレイン酸ナトリウムまたはNaPOPG
c)有機溶媒(例えばエタノールおよび/またはプロピレングリコールを含む)
(ただし、有効成分と安定化剤の重量比は400:1〜10:1である)
を含有する濃縮液をプラセボ脂肪エマルションに混合する段階を含む。
a)例えば臓器または組織同種または異種移植拒絶などの移植拒絶の処置および予防、例えば心臓、肺、同時心肺、肝臓、腎臓、膵臓、皮膚または角膜移植などの受容者の処置。それらは、また、例えば骨髄移植後の移植片対宿主疾患の予防にも適応される。
b)自己免疫疾患および炎症症状、特に関節炎(例えば、慢性関節リウマチ、進行性慢性関節炎および変形性関節炎)およびリウマチ疾患などの自己免疫因子を含む病因をもつ炎症症状の処置および予防。本発明の化合物を使用し得る特定の自己免疫疾患には、自己免疫血液障害(例えば、溶血性貧血、再生不良性貧血、先天性形成不良性貧血および特発性血小板減少症)、全身性エリテマトーデス、多発性軟骨炎、スクレロドーマ(sclerodoma)、ウェゲナー肉芽腫症、皮膚筋炎、慢性活動性肝炎、重症筋無力症、乾癬、スティーブン−ジョンソン症候群、特発性スプルー、自己免疫炎症性腸疾患(例えば、潰瘍性大腸炎およびクローン病を含む)、内分泌性眼病、グレーヴズ病、サルコイドーシス、多発性硬化症、原発性胆汁性肝硬変、若年性糖尿病(I型糖尿病)、ブドウ膜炎(前部および後部)、乾性角結膜炎および春季角結膜炎、間質性肺繊維症、乾癬性関節炎、糸球体腎炎(例えば特発性ネフローゼ症候群または最小変化の腎症を含むネフローゼ症候群を伴うおよび伴わないもの)および若年性皮膚筋炎を含む。
c)喘息の処置および予防。
d)多剤耐性(MDR)の処置。従って、かかる組成物は、多剤耐性癌または多剤耐性AIDSなどの多剤耐性症状の処置および制御において、他の化学療法剤の効力を増強するのに有用である。
e)例えば癌、過増殖皮膚疾患等の増殖性疾患の処置。
f)真菌感染の処置。
g)炎症の処置および予防、特にステロイドの作用の増強。
h)感染、特にMipまたはMip様因子を有する病原体による感染の処置および予防。
i)FK−506および他のマクロフィリン結合性免疫抑制剤の過剰投与の処置。 本明細書に開示したアスコマイシン、FK506またはアスコマイシン誘導体の組成物は、例えば、炎症性および過増殖性皮膚疾患および免疫が関与する疾患の皮膚発現の処置に有用である。より具体的には、本発明の組成物は抗炎症剤および免疫抑制剤および抗増殖剤として、炎症症状および免疫抑制を必要とする症状の予防および処置、例えば
a)−心臓、腎臓、肝臓、骨髄および皮膚などの臓器または組織移植の拒絶、
−例えば骨髄移植後の移植片対宿主疾患、
−例えば慢性関節リウマチ、全身性エリテマトーデス、橋本甲状腺炎、多発性硬化症、重症筋無力症、I型糖尿病およびブドウ膜炎などの自己免疫疾患、
−免疫が関与する疾患の皮膚発現
の予防および処置;
b)例えば乾癬、アトピー性皮膚炎、接触皮膚炎、さらに湿疹様皮膚炎、脂漏性皮膚炎、扁平苔癬、天疱瘡、水疱性類天泡瘡、表皮水疱症、蕁麻疹、血管浮腫、脈管炎(vasculitides)、紅斑、皮膚好酸球増加症、エリテマトーデスおよびざ瘡などの炎症性および過増殖皮膚疾患の処置;および
c)円形脱毛症
に使用するのに有用である。
−有効成分濃縮液中に添加剤がほとんど含まれないこと;
−即使用型エマルションが迅速に形成されること;
−即使用型エマルション中において有効成分が全く沈殿しないこと;
−即使用型エマルション中において液滴サイズ分布が狭いこと;
−エマルション中の有効成分濃度が高いこと;および
−プラセボエマルションと有効成分濃縮液とを混合し、穏やかに撹拌した後、直ちにこの脂肪エマルションを使用できることが含まれる。
実施例1の濃縮液を、例えば希釈率約17で注入することにより、リポフンディン(登録商標)MCT10%、すなわちプラセボ脂肪エマルションに導入すると以下の組成が得られる:
溶解PSC833(括弧内の数値は濾
過開始後の時間)
有効成分と安定化剤の比
実施例8
実施例9
実施例10
実施例11
実施例12
#NaOL=オレイン酸ナトリウム;PG=プロピレングリコール;EtOHAbs=無水エタノール;EtOH90=水10%含有エタノール;RT=室温
平均粒子サイズ(250mm)および粒子サイズ分布(単蜂形分布、全ての粒子が500mmよりも小さい)を光子相関分光測定法で決定した。
ビーグル犬を用いて、対照として経口剤形を用いて、使用した静脈内投与した脂肪エマルションキャリヤーが消失動態に影響を及ぼすかどうかを決定するために、薬物動態学的研究を行った。下記の組成物を調製した:
13a (「低脂肪」形)
脂肪エマルション中100mgPSC833:上記5および6番の濃縮 組成物1mLを10部のリポフンディンMCT10%で希釈した。
13b (「高脂肪」形)
脂肪エマルション中100mgPSC833:上記5および6番の濃縮 組成物1mLを20部のリポフンディンMCT10%で希釈した。
13c 200mgのPSC833を、2個の硬ゼラチンカプセル剤を用いて経 口飲料で投与する。
プロピレングリコール 96mg
ラブラフィルM2125CS 150mg
(内部エステル化コーン油)
クレモフォアRH40 524mg
(ポリオキシル−40硬化ヒマシ油)
PSC833 100mg
DL−α−トコフェロール 1mg
無水エタノール 104mg
脂肪エマルションは、公開欧州特許出願EP569337の実施例6dおよび7lで開示された化合物(化合物A)を有効成分として用いて調製する。
有効成分として化合物Aを含有する濃縮液
脂肪エマルション中化合物A*の可溶化の決定:濃縮液中の添加剤の影響。組成物14aは本発明に記載のものである
*有効成分添加脂肪エマルションを0.2μフィルター(ヌクレオポアフィルター)を通して濾過する
#NaOL=オレイン酸ナトリウム;PG=プロピレングリコール;EtOHAbs=無水エタノール
有効成分PSCを40−O−(2−ヒドロキシ)エチルラパマイシン(実施例15〜24)、32−デオキソラパマイシン(実施例25〜34)、16−ペント−イニルオキシ−32(S)−ジヒドロラパマイシン(実施例35〜44)、および33−エピ−クロロ−33−デスオキシ−アスコマイシン(実施例45〜54)で置きかえて、別の有効成分の上記組成物3〜12に類似した組成物を調製する。それぞれの有効成分濃縮液をプラセボ脂肪エマルションに注入して混合すると、安定なエマルション組成物が迅速に得られる。
Claims (7)
- 有効成分としてラパマイシンまたはその誘導体を含有するエマルション組成物の調製法であって、
a)有効成分、
b)オレイン酸ナトリウムおよびNaPOPG(パルミトイルオレオイルホスファチジルグリセロールナトリウム)から選択される安定化剤、および
c)有機溶媒
を含有し、有効成分と安定化剤との重量比が400:1ないし0.5:1である濃縮液を、プラセボ脂肪エマルションに混合する段階を含む方法。 - 有機溶媒がエタノールおよび/またはプロピレングリコールを含むものである、請求項1に記載の方法。
- 有効成分がラパマイシン、40−O−(2−ヒドロキシ)エチルラパマイシン、32−デスオキシラパマイシンまたは16−ペント−2−イニルオキシ−32(S)−ジヒドロラパマイシンである、請求項1または2に記載の方法。
- a)有効成分としてのラパマイシンまたはその誘導体、
b)オレイン酸ナトリウムおよびNaPOPG(パルミトイルオレオイルホスファチジルグリセロールナトリウム)から選択される安定化剤、および
c)有機溶媒
を含有し、有効成分と安定化剤との重量比が400:1ないし0.5:1である、静脈投与用エマルション組成物を調製するための濃縮液。 - 有機溶媒がエタノールおよび/またはプロピレングリコールを含むものである、請求項4に記載の濃縮液。
- 有効成分と安定化剤との重量比が400:1ないし10:1である、請求項4または5に記載の濃縮液。
- 有効成分がラパマイシン、40−O−(2−ヒドロキシ)エチルラパマイシン、32−デスオキシラパマイシンまたは16−ペント−2−イニルオキシ−32(S)−ジヒドロラパマイシンである、請求項4〜6のいずれかに記載の濃縮液。
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JP4077386B2 true JP4077386B2 (ja) | 2008-04-16 |
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JP2007161630A Pending JP2007246543A (ja) | 1996-01-19 | 2007-06-19 | 医薬組成物 |
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US (2) | US6239102B1 (ja) |
EP (4) | EP0874621B1 (ja) |
JP (2) | JP4077386B2 (ja) |
KR (1) | KR100485146B1 (ja) |
AT (4) | ATE304842T1 (ja) |
AU (1) | AU1543497A (ja) |
CA (2) | CA2678707A1 (ja) |
DE (3) | DE69721729T2 (ja) |
DK (4) | DK1273289T3 (ja) |
ES (4) | ES2247245T3 (ja) |
GB (1) | GB9601120D0 (ja) |
HK (3) | HK1053973B (ja) |
PT (2) | PT1679064E (ja) |
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