JP5375611B2 - 骨同化作用を有するタンパク質のための薬物送達方法 - Google Patents
骨同化作用を有するタンパク質のための薬物送達方法 Download PDFInfo
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- JP5375611B2 JP5375611B2 JP2009531434A JP2009531434A JP5375611B2 JP 5375611 B2 JP5375611 B2 JP 5375611B2 JP 2009531434 A JP2009531434 A JP 2009531434A JP 2009531434 A JP2009531434 A JP 2009531434A JP 5375611 B2 JP5375611 B2 JP 5375611B2
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- 229960004906 thiomersal Drugs 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
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- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
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Description
本出願は、2006年10月3日に出願された米国特許仮出願第60/848,960号の恩恵を主張する。上記出願の全教示は、本明細書中に参照によって援用される。
副甲状腺ホルモン関連タンパク質(「PTHrP」)は、139〜173アミノ酸タンパク質である。PTHrPおよび特定のアナログは、骨粗鬆症および関連障害の治療において骨量および骨の質の向上に有用であることが公知である。しかしながら、薬剤としてのこれらのタンパク質の商業的使用には、保存安定性および調製の容易さに関して許容され得る製剤の開発が必要である。
本発明は、骨粗鬆症を治療するため、骨量を増加するためまたは骨の質を増加するための、副甲状腺ホルモン関連タンパク質(PTHrP)アナログを含む保存安定性の組成物、ならびに本明細書に記載の該アナログおよび該アナログを含む組成物の使用方法を提供する。該組成物は、滅菌形態で保存安定性であり、一般に室温で少なくとも数週間保存され得、ヒト患者への簡便な非経口投与が可能になる。
天然のhPTHrP(1〜34)の配列は以下の通りである:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His Thr Ala (配列番号:1)。
(200μl〜1.6mlの注射により)10〜80μg/日の用量を提供する2ml(=50μg/ml)の1つのバイアル、または
(250μl〜2mlの注射により)5〜40μg/日の用量を提供する5ml(=20μg/ml溶液)の1つのバイアルを得た。
以下の表3より、メチルパラベン(Methyparaben)およびベンジルアルコールは、沈殿および/または保存料の活性の不活性化が見られたので、Glu22,25、Leu23,28,31、Aib29、Lys26,30]hPTHrP(1〜34)NH2(配列番号:2)と共に使用するには適切な保存料ではないと示される。
表6は、実施例4に記載された製剤の化学安定性を詳細に示す。
Claims (22)
- a) 配列[Glu22,25、Leu23,28,31、Aib29、Lys26,30]hPTHrP(1〜34)NH2(配列番号:2)を有するPTHrPアナログ;および
b) pHを4.5〜5.6の範囲に維持するのに有効な量のpHバッファー
を含む、被験体への投与に適した保存安定組成物。 - 前記pHが5.1である、請求項1記載の保存安定組成物。
- 前記pHバッファーが、酢酸バッファー、酒石酸バッファー、リン酸バッファーおよびクエン酸バッファーからなる群より選択される、請求項1記載の保存安定組成物。
- 前記pHバッファーが酢酸バッファーである、請求項3記載の保存安定組成物。
- 前記酢酸バッファーが、酢酸および酢酸ナトリウムである、請求項4記載の保存安定組成物。
- 前記バッファーが1mM〜10mMの濃度範囲で存在する、請求項5記載の保存安定組成物。
- 前記バッファーが6mMの濃度で存在する、請求項6記載の保存安定組成物。
- さらに、有効量の抗菌剤を含む、請求項1記載の保存安定組成物。
- 前記抗菌剤がフェノールである、請求項8記載の保存安定組成物。
- 前記フェノールが0.25〜5mg/mLの濃度で存在する、請求項9記載の保存安定組成物。
- 前記フェノールが5mg/mLの濃度で存在する、請求項10記載の保存安定組成物。
- 前記PTHrPアナログが2mg/mLの濃度で存在する、請求項1記載の保存安定組成物。
- 化学安定剤を含まない、請求項1記載の保存安定組成物。
- 骨粗鬆症の治療が必要な被験体における骨粗鬆症の治療剤の製造のための、
a) 配列[Glu22,25、Leu23,28,31、Aib29、Lys26,30]hPTHrP(1〜34)NH2(配列番号:2)を有するPTHrPアナログ;および
b) pHを4.5〜5.6の範囲に維持するのに有効な量のpHバッファー
を含む保存安定組成物の使用。 - 骨成長の刺激が必要な被験体における骨成長の刺激剤の製造のための、
a) 配列が[Glu 22,25 、Leu 23,28,31 、Aib 29 、Lys 26,30 ]hPTHrP(1〜34)NH 2 (配列番号:2)であるPTHrPアナログ;および
b) pHを4.5〜5.6の範囲に維持するのに有効な量のpHバッファー
を含む保存安定組成物の使用。 - 前記保存安定組成物が、40〜45μgの[Glu22,25、Leu23,28,31、Aib29、Lys26,30]hPTHrP(1〜34)NH2(配列番号:2)を含む量で、皮下注射によって前記被験体に投与される、請求項14または15記載の使用。
- 前記保存安定組成物が、75〜80μgの[Glu22,25、Leu23,28,31、Aib29、Lys26,30]hPTHrP(1〜34)NH2(配列番号:2)を含む量で、皮下注射によって前記被験体に投与される、請求項14または15記載の使用。
- 前記保存安定組成物が、さらに0.25〜5mg/mLの濃度のフェノールを含む、請求項16または17記載の使用。
- 前記pHバッファーが酢酸バッファーである、請求項18記載の使用。
- 前記被験体が骨折を有する、請求項15記載の使用。
- 前記皮下注射が、1日に1回、2日に1回、1週間に2回、1週間に1回、2週間に1回、または1ヶ月に1回である、請求項16または17記載の使用。
- 前記皮下注射が1日に1回の皮下注射である、請求項16または17記載の使用。
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PCT/US2007/021216 WO2008063279A2 (en) | 2006-10-03 | 2007-10-03 | A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof |
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