JP6464145B2 - 成長ホルモン化合物製剤 - Google Patents
成長ホルモン化合物製剤 Download PDFInfo
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- JP6464145B2 JP6464145B2 JP2016505837A JP2016505837A JP6464145B2 JP 6464145 B2 JP6464145 B2 JP 6464145B2 JP 2016505837 A JP2016505837 A JP 2016505837A JP 2016505837 A JP2016505837 A JP 2016505837A JP 6464145 B2 JP6464145 B2 JP 6464145B2
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- growth hormone
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- albumin
- conjugate
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- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Description
配列番号1:成熟hGH 1〜191(ソマトトロピン)(本明細書において、短縮してhGHと呼ばれる)
FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF
組換えhGHに対して成長ホルモン アルブミン-結合剤 コンジュゲートのより低頻度の投与に対応するために、コンジュゲートは、十分に高い濃度で製剤化されなければならない。コンジュゲートの濃度は、mg/mL又はモル濃度で表すことができ、後者は、アルブミン結合剤側鎖に依存する様々な分子量のため、より正確であるとみなすことができる。
(式中、
GHは、成長ホルモンポリペプチドを表し、
Aは、アルブミン結合残基であり、
Bは、(親水性)スペーサーであり、
Wは、A及びBを連結する化学基であり、
Qは、GH及びBを連結する化学基-NH-C(O)-(CH2)-であり、
「-」は、共有結合である)
を有する成長ホルモン アルブミン結合剤 コンジュゲートを含む。
から選択される。
(式中、X1、X2及びX3は、独立して、原子価結合、並びに全てペプチド結合により連結されてもよい-OEG-、-Lys-、-Glu-及び-γ-Glu-のエレメントから選択され、X3は、好ましくは-OEG-又は-Lys-である)
を有する。
(式中、
X4は、-NH-CH(-COOH)-(CH2)4NH-であり、
X3は、-OEG-であり、
X2は、-γ-Glu-γ-Glu-であり、
X1は、-OEG-である)
を有する。
(式中、
X4は、-NH-CH(-COOH)-(CH2)4NH-であり、
X3は、-OEG-であり、
X2は、-γ-Glu-γ-Glu-であり、
X1は、原子価結合である)
を有する。
(式中、
X1は、-W1-[(CHR1)l1-W2]m1-{[(CH2)n1E1]m2-[(CHR2)l2-W3]m3}n2-であり、
X2は、-[(CHR3)l3-W4]m4-{[(CH2)n3E2]m5-[(CHR4)l4-W5]m6}n4-であり、
X3は、-[(CHR5)l5-W6]m7-であり、
l1、l2、l3、l4及びl5は、独立して、0〜16から選択され、
m1、m3、m4、m6及びm7は、独立して、0〜10から選択され、
m2及びm5は、独立して、0〜16から選択され、
n1、n2、n3及びn4は、独立して、0〜6から選択され、
R1、R2、R3、R4及びR5は、独立して、水素、-C(O)OH、-C(O)NH2、-S(O)OH、-S(O)2OH、-CH2S(O)2OH、-NH-C(=NH)-NH2又はC1〜6-アルキルから選択され;アルキル基は、任意選択で、-C(O)OH、-C(O)NH2、-S(O)OH、-S(O)2OH、-CN又は-OHで置換されてもよく、
E1及びE2は、独立して、-O-、-N(R6)-、-N(C(O)R7)-又は原子価結合から選択され、R6及びR7は、独立して、水素又はC1〜6-アルキルを表し、
W1からW6は、独立して、-C(O)NH-、-NHC(O)-、-(CH2)s1C(O)NH-、-C(O)NHCH2-、-CH2NHC(O)-、-C(O)NHS(O)2-、-S(O)2NHC(O)-、-OC(O)NH-、-NHC(O)O-、-C(O)CH2-、-CH2C(O)-、-C(O)CH=CH-、-CH=CHC(O)-、-(CH2)s2-、-C(O)-、-C(O)O-、-OC(O)-、又は原子価結合から選択され;s1及び2は、独立して、0、1、2、3又は4である)
を有する。
から選択される。
本明細書において上述されたように、本発明は、成長ホルモンコンジュゲートと、製剤を安定化することができる界面活性剤とを含む医薬組成物に関する。
医薬組成物の調製の出発点として、成長ホルモン アルブミン結合剤 コンジュゲートは、溶液、通常は水溶液として提供される。この出発溶液は、好ましくは、医薬組成物の調製中の希釈を可能とするために、高濃縮されている。一実施形態では、成長ホルモン アルブミン結合剤 コンジュゲートの出発溶液は、15mg/mL超、例えば15〜30mg/mL、又は例えば15〜25mg/mLである。
背景技術の項において説明されたように、成長ホルモン生成物は、成長ホルモン欠損症の治療に好適である。基本的に、本発明による医薬組成物は、患者が循環成長ホルモン活性の増加から利益を受ける任意の疾患又は障害の治療における使用のためのものであってもよい。この治療において、成長ホルモンタンパク質が投与される。代替として、成長ホルモン活性を提供するために、長期半減期を有する成長ホルモン化合物が投与されてもよい。
1. a)2〜20mg/mLの成長ホルモン アルブミン-結合剤 コンジュゲートと、
b)0.5〜5.0mg/mLの界面活性剤と
を含む医薬組成物。
A-W-B-Q-GH
(式中、
GHは、成長ホルモンタンパク質/化合物を表し、
Aは、アルブミン結合残基であり、
Bは、(親水性)スペーサーであり、
Qは、GH及びBを連結する化学基であり、
Wは、B及びAを連結する化学基であり、
「-」は、共有結合である)
を有する、実施形態1から31のいずれか一項に記載の組成物。
から選択される、実施形態32又は33又は34に記載の組成物。
(式中、Waは、-C(O)NH-、-NHC(O)-、-C(O)NHCH2-、-CH2NHC(O)-、-C(O)NHS(O)2-、-S(O)2NHC(O)-、-OC(O)NH-、-NHC(O)O-、-C(O)CH2-、-CH2C(O)-、-C(O)CH=CH-、-CH=CHC(O)-、-(CH2)-、-C(O)-、-C(O)O-及び-OC(O)-から選択され、
Wbは、-CH2-C6H12-C(=O)-、-OEG-、-Lys、-Glu、-γ-Glu-、-CH-、-CH-(CH2-SO3H)-C(O)-、-S(O)2-(CH2)3-C(O)-及び原子価結合から選択される)
を有する、実施形態32から36のいずれか一項に記載の組成物。
1〜3mg/mLのポロキサマー188と、
0.5〜1.0mg/mLのヒスチジン緩衝剤と、
40-45mg/mLのマンニトールと、
3〜4mg/mLのフェノールと
を含む医薬組成物。
成長ホルモンタンパク質をコードする遺伝子を、組換えによりプラスミドベクターに挿入する。その後、プラスミドベクターを使用して、好適な大腸菌株を形質転換する。N末端メチオニンを用いて、又はその後MEAE配列が切断されるMEAE融合体として、ヒトGH又はGH変異体を発現させることができる。
上述のような最初の精製後、変異体は、その遊離システインの一部がグルタチオン及びシスタミンによりブロックされ得る。非ブロック化は、GSH及びGSSGを含有する平衡緩衝液中で、グルタレドキシンII(Grx2)を使用して酵素的に行われる。非ブロック化されたGH(L101C)は、Sephadex G25カラムで交換された緩衝液により、低分子量GSH/GSSGから分離される。
MALDI-MSを使用して、無傷の精製されたタンパク質を分析し、観察された質量がアミノ酸配列から導出された理論質量に対応したことを確認する。予測される結合であるジスルフィド結合は、トリプシン及びAspN分解に続く、DTTによるジスルフィド結合の還元前及び還元後の分解物のMALDI-MS分析を使用したペプチドマッピングにより実証され得る。
側鎖(I)
4-(1H-テトラゾール-16-イル-ヘキサデカノイルスルファモイル)ブタノイル-OEG-γGlu-γGlu-OEG-Nε(C(O)CH2Br)Lys-OH (I):
上記と同様の様式で、Fmoc-Lys(Mtt)-OH及びWang樹脂を使用して以下の側鎖(II)を調製した。TOF-MS:質量844.84(M+1)
内部遊離単一cys(GH-SH)を有するGHタンパク質の、上述のようなアルブミン結合側鎖(AB-Halo)とのカップリング。
a)好適な選択的還元剤を用いたジスルフィド(VI)の還元によるGH-SH(VII)の放出:
b)ABが単一Cys残基の「-S-」に結合した成長ホルモンコンジュゲートを生成する、ハロゲン活性化アルブミン結合剤(VIII)による遊離GH-SH(VII)のアルキル化。
アルブミン結合剤側鎖(78mg/5等量)を、5%のヒドロキシプロピル-β-シクロデキストリンを含む170mLのHEPES/EDTA緩衝液中に溶解し、MTP(2.1mL、1%)及び0.5MのNaCl(6.34g)を添加する。この混合物に、濃縮GH(L101C)(1等量、46mL)を添加し、混合物を室温で一晩静置した。溶液は、一晩で濁った。HPLCは、未反応の出発材料を示したため、最小量のNMPに溶解した5等量の実施例5からのアルブミン結合剤を更に添加した。得られた混合物を室温で更に16時間撹拌した。コンジュゲーション及び精製の方法に関するさらなる詳細は、WO11/089255を参照されたい。
分析手順は、サイズ排除クロマトグラフィー(SE-HPLC)試験であり、試料はTSK G2000 SWxlカラム、リン酸ナトリウム/イソプロパノール緩衝液を使用した定組成溶離、及びその後の215nmでのUV検出を使用して分析される。全積分面積に対して%HMWPが計算される。
ガラスバイアル又はカートリッジ(I型)内に保存された試料(2mLの最小体積)を、アーキテクトランプ下及びライトチャンバ内で検査する。試料の視覚的外観は、1から5のスコアの透明性及び粒子の基準を有する視覚的スコアにより定量されるが、1は透明で粒子を含まず、5は視認され得る沈殿物を有する試料を指す。
Varian Cary 100 Bio UV-VIS分光光度計を使用して、340nmで試料の光学密度を測定する。
Micro-Flow Imagingフロー顕微鏡MFI 5000において、フロー顕微鏡法を使用して未希釈溶液(1mL)中でのサイズ及び形態による粒子の定量を行った。2μm超、10μm超及び25μm超の視認できない粒子の定量及び特性決定を行った。最終的な気泡及びシリコン液滴を除去するフィルタ(真円度0〜0.85)もまた適用した。
異なる界面活性剤並びに界面活性剤及び緩衝剤(ヒスチジン)濃度の変化を含む上述のコンジュゲートIの製剤の安定性を、異なるpH(pH6.0及び6.6)で調査した。試験は、実験(DoE)試験のデザインとして行った。
コンジュゲートIの製剤の調製において製造可能性試験を行った。
マンニトール及びフェノールを含むヒスチジン緩衝剤(0.68mg/mLヒスチジン、44mg/mLマンニトール、及び3mg/mLフェノール)中のポロキサマー188(1.0mg/mL、3.0mg/mL及び5.0mg/mL)の濃度を変化させて、コンジュゲートIの製剤を作製した。HMWPを測定することにより、pH6.2、6.8、及び7.4における30℃での安定性を試験した。試験は、実験(DoE)試験のデザインとして行った。
以下の実験において、pH6.2、6.5及び6.8での効果を試験した。ポロキサマー188の濃度を変化させて(0.0mg/mL、1.0mg/mL、3.0mg/mL)、またpHを変化させて(6.2、6.5及び6.8)、コンジュゲートI製剤を作製した。試験された組成物の他の成分は、実施例3の通りであった。試料に、室温で7日間、せん断により物理的ストレスを加えた。3時間及び6時間後、並びに1日、2日、5日、6日及び7日後に試料を採取した。他の試料には、25回のピペッティングによりストレスを与えた。全ての試料を視覚的に検査し、更に340nmでのOD(光学密度)を分析した。
3つの追加的な成長ホルモン化合物を使用して、pH6.2及び6.8での実施例4と同様の実験を行った。野生型ヒト成長ホルモン(WT hGH)、コンジュゲートI、及びコンジュゲートIのGHタンパク質でもある101 Cys突然変異(GH L101C)を含む成長ホルモン変異体。図5A、図5B及び図5Cから分かるように、上記の結論が確認された。低い界面活性剤含量は、7日間の間試験されたように、初期及びストレス後の両方の組成物の安定性を改善する。コンジュゲートIの場合、ポロキサマーを含まない試料は、特にpHに依存するようであった。視覚的スコア化により、pHの低下と共に濁度の増加が観察された。
Micro-flow Imaging(MFI)評価を使用して、成長ホルモン組成物中の粒子形成を測定した。Micro-Flow Imagingフロー顕微鏡MFI 5000において、試料(1mL)を測定した。上述のように、以下の化合物が評価に含められた:野生型ヒト成長ホルモン(hGH)、コンジュゲートI、コンジュゲートII及び成長ホルモン変異体L101C(GH L101C)。
無作為化二重盲検プラセボ対照複数投薬及び用量漸増試験を、日本人及び非アジア系健常男性対象において行い、安全性、耐容性並びに薬力学的(PK)及び薬物動態学的(PD)パラメータを評価した。
医薬組成物は、成長ホルモン アルブミン-結合剤 コンジュゲートの調製物を、必要な賦形剤と混合することにより調製されてもよい。以下のプロセスは、コンジュゲートの液体調製が出発点である場合に有用である。
成長ホルモンコンジュゲートI(6.7mg/ml)
1.0mg/mlのポロキサマー188
0.68mg/mlのヒスチジン
44mg/mlのマンニトール
4.0mg/mlのフェノール
製剤化のためのpHは6.8である。
21.3mg/ml及び20.5mg/mlの成長ホルモンコンジュゲートI(0.68mg/mlのヒスチジン中)(バッチNLfK040501及びNLfK040503)
20mg/mlのポロキサマー188(WFI中)
緩衝液:110mg/mlのマンニトール、10mg/mlのフェノール及びヒスチジン。ヒスチジン濃度は、使用されるDSの体積/量に依存する。
pH調節用のHCl
別の試験において、フェノールをフェノール-緩衝溶液中に様々な濃度(5mg/ml、10mg/ml及び30mg/ml)で含め、コンジュゲートI調製物に導入した。以下で分かるように、30mg/mlのフェノールの使用は、最終製剤中の%HMWPの増加をもたらした。HMWPのレベルは、溶液中のコンジュゲートIの濃度及びフェノールの濃度に依存する。
コンジュゲートI調製物(バッチIHJe12-021):18.0mg/ml
フェノール溶液30mg/ml、10mg/ml及び5mg/ml
50mg/mlのポロキサマー
マンニトール(粉末)。
ヒスチジン
2.0mg/ml、3.3mg/ml;6.7mg/ml;及び10mg/mlの成長ホルモンコンジュゲートI
1.0mg/mlのポロキサマー188
0.68mg/mlのヒスチジン
44mg/mlのマンニトール
3.0mg/mlのフェノール
pH6.3。
Claims (28)
-
- 0.5〜4.0mg/mLのポロキサマーを含む、請求項1に記載の医薬組成物。
- 1.0〜3.0mg/mLのポロキサマーを含む、請求項1に記載の医薬組成物。
- ポロキサマー188を含む、請求項1から3のいずれか一項に記載の組成物。
- ヒスチジン緩衝剤を含む、請求項1から4のいずれか一項に記載の組成物。
- グリシンを含まない、請求項1から5のいずれか一項に記載の組成物。
- pHが6.8である、請求項1から6のいずれか一項に記載の組成物。
- 2.0〜4.0mg/mLのフェノール又は3.0〜4.0mg/mLのフェノールを含む、請求項1から7のいずれか一項に記載の組成物。
- 等張剤を含む、請求項1から8のいずれか一項に記載の組成物。
- 等張剤、例えば、20〜50mg/mL又は40〜45mg/mLのマンニトールを含む、請求項1から9のいずれか一項に記載の組成物。
- 成長ホルモン-アルブミン結合剤 コンジュゲートが、式AB-GHで表されるように、互いに共有結合(-)した、アルブミン結合側鎖(AB)及び成長ホルモンタンパク質(GH)を含む、請求項1から10のいずれか一項に記載の組成物。
- AB-が、GHにおけるcys残基を介してGHに結合している、請求項1から11のいずれか一項に記載の組成物。
- GHが、ヒト成長ホルモンと比較して、少なくとも1つの点突然変異を含む、請求項1から12のいずれか一項に記載の組成物。
- GHが、ヒト成長ホルモンと比較して、アミノ酸AA98〜105のいずれか1つに1つの点突然変異を含む、請求項1から13のいずれか一項に記載の組成物。
- GHにおける点突然変異が、Cys突然変異である、請求項14に記載の組成物。
- GHが、L101C突然変異を含む、請求項14に記載の組成物。
- AB-が、GHのL101Cに結合している、請求項14から16のいずれか一項に記載の組成物。
- 成長ホルモン-アルブミン結合剤コンジュゲートが、以下の式
A-W-B-Q-GH
(式中、
GHは、成長ホルモンタンパク質/化合物を表し、
Aは、アルブミン結合残基であり、
Bは、親水性スペーサーであり、
Qは、GH及びBを連結する化学基であり、
Wは、B及びAを連結する化学基であり、
「-」は、共有結合である)
を有する、請求項1から17のいずれか一項に記載の組成物。 - A-W-B-Q-が、GHにおけるL101C突然変異に結合している、請求項18に記載の組成物。
- Aが、
から選択される、請求項18又は19に記載の組成物。 - 成長ホルモン-アルブミン結合剤コンジュゲートが、
-
pHが6.5〜7.0である、医薬組成物。 -
pHが6.5〜7.0である、医薬組成物。 - 成長ホルモン欠損症(GHD)又は成人成長ホルモン欠損症(AGHD)の治療方法における使用のための、請求項1から23のいずれか一項に記載の組成物。
- 週1回の投与による治療方法における使用のための、請求項1から24のいずれか一項に記載の組成物。
- 0.01〜0.08mg/kgの投与量の週1回の投与による成長ホルモン欠損症(GHD)又は成人成長ホルモン欠損症(AGHD)の治療における使用のための、請求項1から25のいずれか一項に記載の組成物。
- 成長ホルモン欠損症に罹患した成人患者に週1回投与するための、請求項24〜26のいずれか一項に記載の組成物。
- 成長ホルモン欠損症に罹患した患者に投与される組成物であって、投与量当たり0.01〜0.08mg/kgの成長ホルモン-アルブミン結合剤 コンジュゲートが投与される、請求項24又は25に記載の組成物。
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