JP2014015479A - 副甲状腺ホルモンおよび骨吸収抑制剤を含む複合型薬学的製剤 - Google Patents
副甲状腺ホルモンおよび骨吸収抑制剤を含む複合型薬学的製剤 Download PDFInfo
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- JP2014015479A JP2014015479A JP2013206919A JP2013206919A JP2014015479A JP 2014015479 A JP2014015479 A JP 2014015479A JP 2013206919 A JP2013206919 A JP 2013206919A JP 2013206919 A JP2013206919 A JP 2013206919A JP 2014015479 A JP2014015479 A JP 2014015479A
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- parathyroid hormone
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Abstract
【解決手段】(a)ほぼ6から24カ月の期間にわたる副甲状腺ホルモンの投与、および(b)副甲状腺ホルモンの投与終了後のほぼ12から36カ月の期間にわたる骨吸収抑制剤の投与に関して適合化された製剤である、副甲状腺ホルモンおよび骨吸収抑制剤を含む複合型薬学的製剤。骨吸収抑制剤はビスフォスフォネート、エストロゲン、選択的エストロゲン受容体調節因子たとえばタモキシフェン、カルシトニン等である。
【選択図】なし
Description
成人個体(男性、女性とも)において、骨は絶えず再構築を受けている。これは、骨の活動性細胞、すなわち骨形成性の骨芽細胞および骨吸収性の破骨細胞の協調的な作用によって、骨吸収が骨形成と密接に関連づけられる過程である。これらの細胞は集合して、いわゆる基底多細胞(代謝)単位(basal multicellular(metabolic)unit)すなわちBMUを形成する。再構築過程は、被覆細胞(lining cell)(非石灰化骨(unmineralized bone)を覆う細胞)の活性化に始まる。被覆細胞は非石灰化骨を吸収した後に収縮して破骨細胞が進入する余地をもたらし、破骨細胞は古い石灰化骨を吸収して同じ部位に骨芽細胞を誘引する環境を作り出す。その後、骨芽細胞は有機基質を構築し、これが後に石灰化されて新骨を形成する。このため、この結果生じる骨量は、破骨細胞による吸収と骨芽細胞による形成とのバランスによって決定される。
骨減少および骨粗鬆症の予防および治療のために、例えばエストロゲン、ビタミンD、およびアレンドロネートなどのビスフォスフォネートといった数多くの薬剤が用いられている(総説については、骨粗鬆症(Osteoporosis)(Marcus, R., Feldman, D.およびKelsey, F.編)Academic Press, San Diego, 1996(非特許文献1)を参照されたい)。この種の薬剤は主として骨吸収の抑制によって作用する。各再構築サイクルでの吸収量を減らしつつ、形成を元の状態に維持することにより、負の骨バランスを軽減して骨減少を遅らせることが可能となる。同時にそれらは活性化頻度を低下させ、再構築空間が縮小することから骨量の増加もわずかな程度に限定される。
副甲状腺ホルモン(PTH)は、副甲状腺から通常分泌される84アミノ酸からなるポリペプチドである。PTHには血清カルシウムを狭い範囲に維持するという重要な生理的役割がある。さらに、これは間欠的に投与された際に同化作用を有する。このことは多くの動物試験およびオープン臨床試験で詳細に報告されており、これに関してはデンプスター(Dempster, D.W.)らによる最近の総説(Endocrine Reviews 1993, vol.14, 690〜709(非特許文献2))がある。PTHは骨に対して多様な作用を及ぼす。その一部は再構築サイクルを介したものである。PTHは活性化頻度の上昇および1サイクル当たりでの正のバランスの両方をもたらす。
(a)完全長副甲状腺ホルモン、
(b)完全長副甲状腺ホルモンの生物的活性のある変異体、
(c)生物的活性のある副甲状腺ホルモンの断片、および
(d)副甲状腺ホルモンの断片の生物的活性のある変異体。
本文脈において、「生物的活性のある」という用語は、PTH刺激によるアデニル酸シクラーゼ産生に関するラット骨肉腫細胞に基づくアッセイ(Rodanら(1983)J. Clin. Invest. 72, 1511およびRabbaniら(1988)Endocrinol. 123、2709を参照)などの、PTH活性に関するバイオアッセイにおいて十分な反応を誘発するものと理解されるべきである。
骨粗鬆症である閉経後の女性(n=172)に対して、完全型ヒトPTH(1-84)を皮下注射により、1日当たり50から100μgまでの用量で1年にわたり投与した。腰椎における脊椎の骨密度は平均8%増加したことが示された。個々の患者における増加は10%以上とかなり高かった。大腿骨頸部の変化はこれよりも小さく、1から3%の範囲であった。
Claims (37)
- (a)ほぼ6から24カ月の期間にわたる副甲状腺ホルモンの投与、および(b)副甲状腺ホルモンの投与終了後のほぼ6から36カ月の期間にわたる骨吸収抑制剤の投与に関して適合化された製剤である、副甲状腺ホルモンおよび骨吸収抑制剤を含む複合型薬学的製剤。
- ほぼ12から24カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項1記載の複合型薬学的製剤。
- ほぼ18カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項2記載の複合型薬学的製剤。
- ほぼ12から36カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項1から3のいずれか一項に記載の複合型薬学的製剤。
- ほぼ12から18カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項4記載の複合型薬学的製剤。
- ほぼ12カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項5記載の複合型薬学的製剤。
- 副甲状腺ホルモンが以下のものからなる群より選択される、請求項1から6のいずれか一項に記載の製剤:
(a)完全長副甲状腺ホルモン、
(b)完全長副甲状腺ホルモンの生物的活性のある変異体、
(c)生物的活性のある副甲状腺ホルモンの断片、および
(d)副甲状腺ホルモンの断片の生物的活性のある変異体。 - 骨吸収抑制剤がビスフォスフォネートである、請求項1から7のいずれか一項に記載の製剤。
- ビスフォスフォネートがアレンドロネートである、請求項8記載の製剤。
- 骨吸収抑制剤がエストロゲン様効果をもつ物質である、請求項1から7のいずれか一項に記載の製剤。
- エストロゲン様効果をもつ物質がエストロゲンである、請求項10記載の製剤。
- 骨吸収抑制剤が選択的エストロゲン受容体調節因子である、請求項1から7のいずれか一項に記載の製剤。
- 選択的エストロゲン受容体調節因子がラロキシフェン、タモキシフェン、ドロロキシフェン、トレミフェン、イドキシフェンまたはレボルメロキシフェンからなる群より選択される、請求項12記載の製剤。
- 骨吸収抑制剤がカルシトニン様物質である、請求項1から7のいずれか一項に記載の製剤。
- カルシトニン様物質がカルシトニンである、請求項14記載の製剤。
- 骨吸収抑制剤がビタミンD類似体である、請求項1から7のいずれか一項に記載の製剤。
- 骨吸収抑制剤がカルシウム塩である、請求項1から7のいずれか一項に記載の製剤。
- (a)ほぼ6から24カ月の期間にわたる副甲状腺ホルモンの投与、および(b)副甲状腺ホルモンの投与終了後のほぼ12から36カ月の期間にわたる骨吸収抑制剤の投与に関して適合化された医薬品である、骨関連疾患の治療または予防のための医薬品の製造における骨吸収抑制剤と組み合わせての副甲状腺ホルモンの使用。
- 医薬品がほぼ12から24カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項18記載の使用。
- 医薬品がほぼ18カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項19記載の使用。
- 医薬品がほぼ12から36カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項18から20のいずれか一項に記載の使用。
- ほぼ12から18カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項21記載の使用。
- ほぼ12カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項22記載の使用。
- 副甲状腺ホルモンが
(a)完全長副甲状腺ホルモン、
(b)完全長副甲状腺ホルモンの生物的活性のある変異体、
(c)生物的活性のある副甲状腺ホルモンの断片、および
(d)副甲状腺ホルモンの断片の生物的活性のある変異体
から選択される、請求項18から23のいずれか一項に記載の使用。 - 骨吸収抑制剤が請求項8から17のいずれか一項によって定義される、請求項18から24のいずれか一項に記載の使用。
- 骨粗鬆症の治療のための医薬品の製造における請求項18から25のいずれか一項に記載の使用。
- 骨関連疾患の治療または予防の方法であって、該治療を必要とするヒトを含む哺乳動物に対して、請求項1から17のいずれか一項に記載の薬学的製剤の有効量を投与することを含む方法。
- 骨関連疾患の治療または予防の方法であって、該治療を必要とするヒトを含む哺乳動物に対して、(a)ほぼ6から24カ月の期間にわたる副甲状腺ホルモンの有効量、および(b)副甲状腺ホルモンの投与終了後のほぼ6から36カ月の期間にわたる骨吸収抑制剤の有効量を投与することを含む方法。
- ほぼ6から24カ月の期間にわたり副甲状腺ホルモンによる治療をすでに受けた患者に対して、副甲状腺ホルモンの投与終了後にほぼ12から36カ月の期間にわたって骨吸収抑制剤の有効量を投与することを含む、骨関連疾患の治療または予防の方法。
- ほぼ12から24カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項27から29のいずれか一項に記載の骨関連疾患の治療または予防の方法。
- ほぼ18カ月にわたる副甲状腺ホルモンの投与に関して適合化された、請求項30記載の骨関連疾患の治療または予防の方法。
- ほぼ12から36カ月にわたる該骨吸収抑制剤の投与に関して適合化された、請求項27から31のいずれか一項に記載の骨関連疾患の治療または予防の方法。
- ほぼ12から18カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項32記載の骨関連疾患の治療または予防の方法。
- ほぼ12カ月にわたる骨吸収抑制剤の投与に関して適合化された、請求項33記載の骨関連疾患の治療または予防の方法。
- 副甲状腺ホルモンが
(a)完全長副甲状腺ホルモン、
(b)完全長副甲状腺ホルモンの生物的活性のある変異体、
(c)生物的活性のある副甲状腺ホルモンの断片、および
(d)副甲状腺ホルモンの断片の生物的活性のある変異体
から選択される、請求項27から34のいずれか一項に記載の方法。 - 骨吸収抑制剤が請求項8から17のいずれか一項によって定義される、請求項27から35のいずれか一項に記載の方法。
- 骨粗鬆症の治療のための、請求項27から36のいずれか一項に記載の方法。
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