JP2016533345A - 持続型ヒト成長ホルモン製剤 - Google Patents
持続型ヒト成長ホルモン製剤 Download PDFInfo
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- JP2016533345A JP2016533345A JP2016518140A JP2016518140A JP2016533345A JP 2016533345 A JP2016533345 A JP 2016533345A JP 2016518140 A JP2016518140 A JP 2016518140A JP 2016518140 A JP2016518140 A JP 2016518140A JP 2016533345 A JP2016533345 A JP 2016533345A
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- growth hormone
- human growth
- sustained
- conjugate
- hgh
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Abstract
Description
両末端にアルデヒド反応器を有する分子量約3.4 kDaのポリエチレングリコールであるALD−PEG−ALDをヒト成長ホルモン(hGH、分子量22 kDa)と結合させ、これをヒトIgG4由来の非−糖鎖化されたFc領域(約50 kDa)N末端に結合させ、本発明の代表的な持続型ヒト成長ホルモン結合体であるhGH−PEG−Fc結合体(以下、「持続型hGH結合体」と命名)を製造し、精製した。
(1)濃度及び緩衝溶液による持続型hGH結合体の凍結乾燥製剤の安定性の評価
持続型hGH結合体を下記表1のような濃度で含む凍結乾燥製剤を製造した後、再構築(reconstitution)して物質の安定性を確認した。緩衝溶液とpHの変更に伴う持続型hGH結合体の安定化を評価するために、緩衝溶液とpHを変更した製剤の安定性も確認した。
前記試験例1−(1)の製剤である実施例2(20mMのクエン酸ナトリウム、pH 5.2、150 mMの塩化ナトリウム、5%のマンニトール、0.005%のポリソルベート80)、実施例3(20mMの酢酸ナトリウム、pH 5.6、150mMの塩化ナトリウム、5%のマンニトール、0.005%のポリソルベート80)、及び実施例3を基本とした等張性製剤(20mMの酢酸ナトリウム、pH 5.6、4%のマンニトール、0.005%のポリソルベート80)を基にして、持続型hGH結合体を下記表3に示すように、68.25 mg/mL及び58.5 mg/mLの濃度で混合した後、凍結乾燥し、その後に表3の保存剤を含む再構築溶液を使用して溶解時間の測定及び安定性を確認した。製品性状は目視で確認して比較した。凍結乾燥及び再構築方法は、前記試験例1−(1)のように行った。再構築した液状形態の製剤を25℃で4週間保管した後、イオン交換クロマトグラフィー法(Ion exchange chromatography、IE−HPLC)及び目視で性状確認を用いて安定性の評価を行い、その結果を表4に示した。表4のIE−HPLC(%)は、分析の時点における持続型hGH結合体の純度を示す。
持続型hGH結合体を下記濃度別に含む凍結乾燥製剤を製造した後、凍結乾燥物質の製品性状及び再構築溶解度を確認した。前記試験例1−(1)の製剤である実施例1の組成(20mMのクエン酸ナトリウム、pH 5.2、150 mMの塩化ナトリウム、5%のマンニトール、0.005%のポリソルベート80)を基にして、持続型hGH結合体を下記表5のような濃度で混合した後、凍結乾燥し、その後、蒸留水を用いて再構築溶解時間を測定した。凍結乾燥及び再構築方法は、前記試験例1−(1)のように行った。製品性状は目視で確認して比較した。溶解は、自動シェーカーを使用し、振幅60度、30 rpmに設定して再構築した。下記の表6は、溶解が完了するまでにかかる時間を示す。
安定化剤の種類に応じた持続型hGH結合体の凍結乾燥製剤を製造して溶解時間、溶解性状及び持続型hGH結合体の安定性を確認した。凍結乾燥前の予備製剤は、下記表7のような組成で準備し、前記製剤で78.0 mg/mLの持続型hGH結合体を凍結乾燥した後、蒸留水を用いて再構築し、この時の再構築に伴う溶解時間を評価した。凍結乾燥及び再構築方法は、前記試験例1−(1)のように行った。製品性状は目視で確認して比較した。溶解は、自動シェーカーを使用し、振幅60度、30 rpmに設定して再構築し、溶解時間を確認した結果を表8に示した。
前記試験例1−(4)で確認された製剤である実施例19の組成(20 mMのクエン酸ナトリウム、pH 5.2、5%(w/v)のマンニトール、5 mMのヒスチジン、0.005%(w/v)のポリソルベート80)に基づいて、持続型hGH結合体の濃度に応じた凍結乾燥物質の溶解度を確認した。下記表10のような組成で予備製剤を製造して凍結乾燥した。凍結乾燥時、予備製剤を蒸留水を用い、それぞれ1倍、1/2倍、1/4倍に希釈して凍結乾燥物質を製造した。乾燥は、1次、2次乾燥に分けて進行し、凍結乾燥の温度勾配は、図1のように設定した。再構築は、希釈する前の体積の量に対応する蒸留水で溶解した。溶解は、自動シェーカーを使用し、振幅60度、30 rpmに設定して再構築した。表11は、溶解が完了するまでにかかる時間を示す。
前記試験例1−(1)の温度勾配設定(図1)で1次乾燥時間を10時間から20時間に増加させ、1次乾燥温度を4℃の一区間を−20℃、−5℃二区間に分けて設定した(図2)。既存の温度勾配の方法では、凍結乾燥物質に水分が3〜5%残っており、凍結乾燥物質が崩壊する現象を示した。温度勾配を、図2のように変更したとき、体積が大きくなっても(〜5mL)、乾燥が完全にされている凍結乾燥物質を確認することができた。
前記試験例1−(1)及び(2)で確認された製剤の組成(20 mMの酢酸ナトリウム、pH 5.6、5%(w/v)のマンニトール、150mMの塩化ナトリウム、0.005%(w/v)のポリソルベート80 )に基づいて浸透圧を考慮した安定化剤の濃度を設定し、それに伴う凍結乾燥物質の溶解度を確認した。下記表12のような組成で予備製剤を製造して凍結乾燥した。
前記試験例1−(7)で確認された製剤(20 mMの酢酸ナトリウム、pH 5.6、5%(w/v)のマンニトール、0.005%(w/v)のポリソルベート80)に基づいてマンニトールの濃度に応じた凍結乾燥物質の溶解度及び浸透圧を確認した。
前記試験例1−(8)で確認された製剤(20 mMの酢酸ナトリウム、pH 5.6、4%(w/v)のマンニトール、0.005%(w/v)のポリソルベート80)に基づいて凍結乾燥物質の4 ℃、25℃保管安定性を確認した。安定性は、凍結乾燥状態で4℃、25℃で6ヶ月間保管した後、再構築し、イオン交換クロマトグラフィー法(Ion exchange chromatography、IE−HPLC)を用いて評価した。初期の再構築溶液は、液状の状態で、25℃で4週間保管した後、再構築し、イオン交換クロマトグラフィー法(Ion exchange chromatography、IE−HPLC)を用いて評価した。表16のIE−HPLC(%)は、分析の時点における凍結乾燥物質の持続型hGH結合体の純度を示す。表17のIE−HPLC(%)は、再構築液状形態の物質の持続型hGH結合体の純度を示す。
(1)pHと緩衝溶液の種類及び等張化剤と糖アルコールの濃度に応じた持続型hGH結合体液状製剤の安定性の評価
本発明において安定化剤として緩衝溶液の種類及び等張化剤と糖アルコールの濃度が持続型hGH結合体の安定性に及ぼす影響を実験した。下記表18のような組成で、25℃で0〜4週間保管した後、イオン交換クロマトグラフィー法、サイズ排除クロマトグラフィー法を用いて分析した。表19及び20では、IE−HPLC(%)とSE−HPLC(%)は、(Area%/ Start Area%)であり、初期結果値に対応した持続型hGH結合体の残存率を示す。表19は、保管した後、持続型hGH結合体のIE−HPLC残存率、表20は、保管した後、持続型hGH結合体のSE−HPLC残存率をそれぞれ示す。
本発明において安定化剤として緩衝溶液の種類が持続型hGH結合体の安定性に及ぼす影響を実験した。試験例2(1)を通じて、選択したpH5.2、4%のマンニトール、0.005%のポリソルベート80を基準にして、下記表21のような組成で、25℃で0〜4週間保管した後、IE−HPLCとSE−HPLCを用いて分析した。表22及び23でIE−HPLC(%)とSE−HPLC(%)は、(Area%/ Start Area%)であり、初期結果値に対応した持続型hGH結合体の残存率を示す。表22は、保管した後、持続型hGH結合体のIE−HPLC残存率、表23は、保管した後、持続型hGH結合体のSE−HPLC残存率をそれぞれ示す。
Claims (49)
- 生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された持続型ヒト成長ホルモン(hGH)結合体、緩衝溶液、非イオン性界面活性剤及び糖アルコールを含有する、持続型ヒト成長ホルモン結合体製剤。
- 前記製剤は、生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された持続型hGH結合体、及び緩衝溶液、非イオン性界面活性剤及び糖アルコールを含有するアルブミン−非含有水溶液を混合した水溶液を凍結乾燥した混合物を含む、持続型ヒト成長ホルモン結合体の凍結乾燥製剤である、請求項1に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液は、酢酸塩、ヒスチジンまたはクエン酸塩緩衝溶液である、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液は、酢酸塩緩衝溶液である、請求項3に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記酢酸塩は、酢酸ナトリウムであり、クエン酸塩はクエン酸ナトリウムである、請求項3に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液のpHは、5.0〜6.0である、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、マンニトールまたはソルビトールである、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、水溶液の総体積に対して1%(w/v)〜10%(w/v)の範囲で含まれる、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、2.5%(w/v)〜5%(w/v)の範囲で含まれる、請求項8に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非イオン性界面活性剤は、ポリソルベート80である、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非イオン性界面活性剤の濃度は、水溶液の総体積に対して0.001%(w/v)〜0.05%(w/v)である、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記アルブミン−非含有水溶液は、糖類、多価アルコール及びアミノ酸で構成される群から選択された一つ以上をさらに含有する、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記アミノ酸は、ヒスチジンまたはグリシンである、請求項12に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記ヒスチジンの濃度は、1〜10mMである、請求項13に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記持続型hGH結合体の濃度は、10〜100mg/mLである、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記アルブミン−非含有水溶液は、さらに等張化剤を含む、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記等張化剤は、塩化ナトリウムである、請求項16に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記塩化ナトリウムの濃度は、0〜200mMである、請求項17に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記凍結乾燥製剤の容器は、バイアル、デュアルチャンバーカートリッジまたはデュアルチャンバーシリンジの形態である、請求項2に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記製剤は、生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された薬理学的有効量の持続型ヒト成長ホルモン(hGH)結合体、及びアルブミン−非含有安定化剤を含み、前記安定化剤は、緩衝溶液、非イオン性界面活性剤及び糖アルコールを含有する持続型ヒト成長ホルモン結合体液状製剤である、請求項1に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記製剤は、等張化剤を含有しない、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液は、クエン酸塩、酢酸塩、またはヒスチジン緩衝溶液である、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、マンニトールまたはソルビトールである、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、2%(w/v)〜4.5%(w/v)の濃度で製剤に含まれる、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記糖アルコールは、4%(w/v)の濃度で製剤に含まれる、請求項24に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液のpHは、5.0〜6.0である、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記緩衝溶液のpHは、5.2である、請求項26に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非イオン性界面活性剤はポリソルベート80である、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非イオン性界面活性剤の濃度は、製剤の総体積に対して0.001%(w/v)〜0.05%(w/v)である、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記持続型hGH結合体は、5.0mg/mL〜60.0mg/mLの濃度で製剤に含まれる、請求項20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記ヒト成長ホルモン(hGH)は、天然型hGHと同一なアミノ酸配列を有する、請求項1、2又は20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記免疫グロブリンFc領域がIgG、IgA、IgD、IgE、またはIgM由来のFc領域である、請求項1、2又は20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記免疫グロブリンFc領域のそれぞれのドメインがIgG、IgA、IgD、IgE、及びIgMからなる群から選択される免疫グロブリンに由来した異なる起源を有するドメインのハイブリッドである、請求項32に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記免疫グロブリンFc領域が同一な起源のドメインからなる短鎖免疫グロブリンで構成された二量体または多量体である、請求項32に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記免疫グロブリンFc領域がIgG4 Fc領域である、請求項32に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記免疫グロブリンFc領域がヒト非糖鎖化IgG4 Fc領域である、請求項32に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記結合体は、ヒト成長ホルモン及び免疫グロブリンFcが非ペプチド性重合体をリンカーにして連結された形態であるか、または遺伝子組換え技術を用いて連結された形態である、請求項1、2又は20に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非ペプチド性重合体は、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコールとプロピレングリコールとの共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、多糖類、デキストラン、ポリビニルエチルエーテル、PLA(ポリ乳酸、polylactic acid)及びPLGA(ポリ乳酸−グリコール酸、polylactic−glycolic acid)のような生分解性高分子、脂質重合体、キチン、ヒアルロン酸、及びそれらの組み合わせで構成された群から選択された、請求項37に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記非ペプチド性重合体は、ポリエチレングリコールである、請求項38に記載の持続型ヒト成長ホルモン結合体製剤。
- 前記製剤は、下垂体性小人症、成長ホルモン欠乏症、プラダー・ウィリー症候群または特発性低身長の治療のためのものである、請求項1、2又は20に記載の持続型ヒト成長ホルモン結合体製剤。
- 生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された持続型ヒト成長ホルモン(hGH)結合体、及び酢酸緩衝溶液、ポリソルベート80、及びマンニトールを含有するアルブミン−非含有水溶液を凍結乾燥した混合物を含む、持続型ヒト成長ホルモン結合体の凍結乾燥製剤。
- 生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された薬理学的有効量の持続型ヒト成長ホルモン(hGH)結合体、及びクエン酸塩緩衝溶液、ポリソルベート80、及びマンニトールを含むアルブミン−非含有安定化剤を含有し、前記安定化剤は、等張化剤を含まないことを特徴とする、持続型ヒト成長ホルモン結合体液状製剤。
- 生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された持続型ヒト成長ホルモン(hGH)結合体、緩衝溶液、非イオン性界面活性剤及び糖アルコールを含有するアルブミン−非含有水溶液を凍結乾燥する段階を含む、請求項2の凍結乾燥製剤の製造方法。
- 請求項2の凍結乾燥製剤に含まれた、生理活性ペプチドであるヒト成長ホルモン(Human Growth Hormone、hGH)と免疫グロブリンFc領域が結合された持続型ヒト成長ホルモン(hGH)結合体、緩衝溶液、非イオン性界面活性剤及び糖アルコールを含有するアルブミン−非含有水溶液を凍結乾燥した混合物に再構築溶液を添加する段階を含む、請求項2の凍結乾燥製剤を再構築する方法。
- 前記再構築溶液は、注射用水である、請求項44に記載の方法。
- 前記再構築溶液は、さらに保存剤を含む、請求項44に記載の方法。
- 前記保存剤は、ベンジルアルコール、m−クレゾールまたはフェノールである、請求項46に記載の方法。
- 前記方法で再構築された製剤は、持続型hGH結合体を10〜100mg/mLの濃度で含む、請求項44に記載の方法。
- 請求項2の凍結乾燥製剤及び再構築溶液を含む、キット。
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KR20130115177 | 2013-09-27 | ||
PCT/KR2014/009059 WO2015046974A1 (ko) | 2013-09-27 | 2014-09-26 | 지속형 인간 성장 호르몬 제제 |
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KR20130049671A (ko) | 2011-11-04 | 2013-05-14 | 한미사이언스 주식회사 | 생리활성 폴리펩타이드 결합체 제조 방법 |
AR090281A1 (es) | 2012-03-08 | 2014-10-29 | Hanmi Science Co Ltd | Proceso mejorado para la preparacion de un complejo polipeptidico fisiologicamente activo |
CA2944138C (en) * | 2014-03-31 | 2023-06-20 | Hanmi Pharm. Co., Ltd. | Method for improving solubility of protein and peptide by using immunoglobulin fc fragment linkage |
KR101808234B1 (ko) | 2015-06-23 | 2017-12-12 | (주)알테오젠 | IgG Fc 도메인을 가지는 융합 단백질의 안정한 액상 제제 |
KR20170079409A (ko) * | 2015-12-30 | 2017-07-10 | 한미약품 주식회사 | 지속형 인간 성장 호르몬 결합체의 신규 액상 제제 |
CN106256835A (zh) * | 2016-08-19 | 2016-12-28 | 安源医药科技(上海)有限公司 | 高糖基化人生长激素融合蛋白及其制备方法与用途 |
KR101861163B1 (ko) | 2017-04-26 | 2018-05-25 | 삼천당제약주식회사 | 안과용 약학 조성물 |
MX2022014669A (es) * | 2020-05-22 | 2023-02-13 | Hanmi Pharm Ind Co Ltd | Formulacion liquida de conjugado de derivado de glucagon de accion prolongada. |
CN115845032A (zh) * | 2022-10-28 | 2023-03-28 | 深圳科兴药业有限公司 | 生长激素fc融合蛋白注射液及其用途 |
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- 2014-09-26 KR KR1020140129476A patent/KR102276304B1/ko active IP Right Grant
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- 2014-09-26 CN CN202210040339.9A patent/CN114288254A/zh active Pending
- 2014-09-26 CN CN201480064028.XA patent/CN105848645A/zh active Pending
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BR112016006455A2 (pt) | 2017-08-01 |
CA2925416A1 (en) | 2015-04-02 |
WO2015046974A1 (ko) | 2015-04-02 |
JP6549104B2 (ja) | 2019-07-24 |
IL244769A0 (en) | 2016-04-21 |
TW201605468A (zh) | 2016-02-16 |
EP3050559A4 (en) | 2017-05-31 |
HK1225976A1 (zh) | 2017-09-22 |
RU2016113684A3 (ja) | 2018-06-28 |
EP3050559A1 (en) | 2016-08-03 |
EP3050559B1 (en) | 2020-06-03 |
KR20150035681A (ko) | 2015-04-07 |
CN105848645A (zh) | 2016-08-10 |
US20160213789A1 (en) | 2016-07-28 |
MX2016003705A (es) | 2016-05-16 |
CN114288254A (zh) | 2022-04-08 |
US20210138070A1 (en) | 2021-05-13 |
KR102276304B1 (ko) | 2021-07-14 |
AR097840A1 (es) | 2016-04-20 |
US10987425B2 (en) | 2021-04-27 |
EP3689335A1 (en) | 2020-08-05 |
RU2016113684A (ru) | 2017-11-01 |
RU2683823C2 (ru) | 2019-04-02 |
AU2014329003A1 (en) | 2016-05-12 |
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