JP5486690B2 - メラノコルチン受容体リガンドの医薬組成物 - Google Patents
メラノコルチン受容体リガンドの医薬組成物 Download PDFInfo
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- JP5486690B2 JP5486690B2 JP2012539052A JP2012539052A JP5486690B2 JP 5486690 B2 JP5486690 B2 JP 5486690B2 JP 2012539052 A JP2012539052 A JP 2012539052A JP 2012539052 A JP2012539052 A JP 2012539052A JP 5486690 B2 JP5486690 B2 JP 5486690B2
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Description
(1)1観点において、本発明は、メラノコルチン受容体の内の1種類以上のリガンドとして作用するペプチドまたはその医薬的に許容できる塩を含む溶液、ゲルもしくは半固体、または懸濁液の医薬組成物に向けられており、ここでそのペプチドは対象への皮下または筋肉内投与の後デポーを形成する。
(4)前記のペプチドがパモ酸塩の形である、前記の段落のいずれか1個に記載の医薬組成物。
(7)前記の有機性ポリマーがPEGである、段落6に記載の医薬組成物。
(9)前記のペプチドをPEG200またはPEG400水溶液中で溶解させ、ここでPEGの水に対する体積対体積比が約1:99から約99:1までである、段落8に記載の医薬組成物。
(12)前記のペプチドの重量対体積濃度が約0.1mg/mL〜約600mg/mLである、前記の段落のいずれか1個に記載の医薬組成物。
(14)前記のArg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2のパモ酸塩をPEG400/水溶液中で溶解させ、ここでPEG400の水に対する体積対体積比が約1:1であり、そのペプチドの重量対体積濃度が約200mg/mLである、段落13に記載の医薬組成物。
(19)前記の保存剤が、m−クレゾール、フェノール、ベンジルアルコール、およびメチルパラベンからなるグループから選択される、段落18に記載の医薬組成物。
(21)さらに等張剤を含む、前記の段落のいずれか1個に記載の医薬組成物。
(23)さらに安定剤を含む、前記の段落のいずれか1個に記載の医薬組成物。
(25)さらに界面活性剤を含む、前記の段落のいずれか1個に記載の医薬組成物。
(27)さらに緩衝剤を含む、前記の段落のいずれか1個に記載の医薬組成物。
(28)前記の緩衝剤がトリス、酢酸アンモニウム、酢酸ナトリウム、グリシン、アスパラギン酸、およびビス−トリスからなるグループから選択される、段落27に記載の医薬組成物。
(30)前記の二価金属が亜鉛である、段落29に記載の医薬組成物。
(31)前記の溶液が透明な液体である、前記の段落のいずれか1個に記載の医薬組成物。
実施例2:Ac-D-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;
実施例3:Ac-Tyr-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;
実施例4:Ac-Tyr-D-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;および
実施例5:ヒダントイン(Arg-Gly)-シクロ(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2。
Ac: アセチル
AlaまたはA: アラニン
ArgまたはR: アルギニン
CysまたはC: システイン
GluまたはE: グルタミン酸
GlyまたはG: グリシン
HisまたはH: ヒスチジン
PheまたはF: フェニルアラニン
TrpまたはW: トリプトファン
TyrまたはY: チロシン
別途示さない限り、この開示における全てのアミノ酸の略語(例えばAla)は-NH-C(R)(R’)-CO-の構造を表し、ここでRおよびR’はそれぞれ独立して水素またはアミノ酸の側鎖(例えば、Alaに関してはR = CH3およびR’ = H)であり、またはRおよびR’は繋がれて環系を形成していてよい。
“-シクロ(Cys-Cys)-”は次の構造を意味する:
本明細書において用いられる特定の他の略語を次のように定義する:
Boc: tert-ブチルオキシカルボニル
BSA: ウシ血清アルブミン
DCM: ジクロロメタン
DIPEA: ジイソプロピルエチルアミン
DMF: ジメチルホルムアミド
DTT: ジチオスレイトール
Fmoc: 9-フルオレニルメチルオキシカルボニル
HBTU: 2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート
HOBt: 1-ヒドロキシ-ベンゾトリアゾール
HPLC: 高速液体クロマトグラフィー
IBMX: イソブチルメチルキサンチン
パモ酸ナトリウム: 次の構造を有するパモ酸二ナトリウム塩
LOQ: 定量限界
MRM: 多重反応モニタリング
NMP: N-メチルピロリドン
PBS: リン酸緩衝生理食塩水
PEG: ポリ(エチレングリコール)、それは次の構造を有する:
PEG400: 約400Daの平均分子量を有するポリ(エチレングリコール)
TFA: トリフルオロ酢酸
TIS: トリイソプロピルシラン
Tris-HCl: トリス(ヒドロキシメチル)アミノメタン塩酸塩
Trt: トリチル。
この発明のペプチドは、標準的な固相ペプチド合成により調製することができる。例えば、Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 第2版 1984)を参照。以下の実施例は、この発明のペプチドを作るための合成法を記述し、その方法は当業者に周知である。他の方法も当業者に既知である。その実施例は説明のために提供するのであって、本発明の範囲を限定することを意味するものでは決して無い。
実施例1の酢酸塩(200 mg, 0.18 mmole)を10 mLの水中で溶解させた。パモ酸ナトリウム(155 mg, 0.36 mmole)を10 mLの水中で溶解させた。その2つの溶液を合わせてよく混合した。沈殿を3000 rpmで20分間の遠心分離により集め、水で3回洗浄し、凍結乾燥により乾燥させた。
本発明の化合物は、下記の手順に従ってメラノコルチン受容体の内の1種類以上のリガンドとしての活性に関して試験することができ、試験した。当業者は、本発明の化合物のメラノコルチン受容体分子への結合活性をアッセイするために、本明細書で記述した手順に類似の手順を用いてよいことを知っているであろう。
インビトロ受容体結合アッセイのために用いられる細胞膜を、hMC-R受容体亜型1、3、4または5を安定して発現するトランスジェニックCHO-K1細胞から得た。望まれるhMC-R受容体亜型を発現するCHO-K1細胞を、氷冷したpH 7.4の50mM Tris-HCl中で超音波処理し(Branson(登録商標),コネチカット州、米国;設定7、おおよそ30秒間)、次いでおおよそ4℃の温度において39,000 gで10分間遠心分離した。そのペレットを同じ緩衝液中で再懸濁し、おおよそ4℃の温度において50,000 gで10分間遠心分離した。細胞膜を含有する洗浄したペレットを、おおよそ−80℃で保管した。
細胞内の環状AMP (cAMP)レベルを、電気化学発光(ECL)アッセイ(Meso Scale Discovery,米国メリーランド州ゲイザースバーグ;以下“MSD”と呼ぶ)により決定した。hMC-R受容体亜型を安定して発現するCHO-K1細胞を、RMPI 1640(登録商標)アッセイ緩衝液(RMPI 1640緩衝液は0.5mM IBMX、および0.2%タンパク質カクテル(MSDブロッカーA)を含有する)中で懸濁した。hMC受容体亜型1、3、4または5を安定して発現するトランスジェニックCHO-K1細胞を、組み込まれた(integrated)炭素電極を含有し、抗cAMP抗体でコートされた384-ウェルMulti-Arrayプレート(MSD)中で、おおよそ7,000細胞/ウェルの密度で分配した。増大する濃度の試験化合物を添加し、その細胞をおおよそ37℃でおおよそ40分間保温した。この保温の後、0.2%タンパク質カクテルおよび2.5 nM TAG(商標)ルテニウム標識cAMP (MSD)を含有する溶解緩衝液(ph 7.3の、MgCl2およびTriton X-100(登録商標)を含むHEPES緩衝生理食塩水溶液)を添加し、細胞を室温でおおよそ90分間保温した。その第2の保温期間の終わりに、読み取り緩衝液(ph 7.8の、ECL共反応物およびTriton X-100を含有するTris緩衝溶液)を添加し、Sector Imager 6000読み取り装置(登録商標)(MSD)を用いたECL検出により、細胞溶解物中のcAMPレベルを直ちに決定した。データをコンピューター支援非線形回帰分析(XL fit; IDBS)を用いて分析し、EC50値またはKb値のどちらかとして報告した。
実施例1のパモ酸塩の配合物の調製
実施例1のパモ酸塩(50mg)を微量遠心チューブの中に量って入れ、125μLのPEG400および125μLの水をその後に添加した。溶解を促進するため、その混合物を超音波処理した。透明な溶液が得られる可能性があり、得られた。
実施例1の以下の“配合物1〜6”を調製した:
(1)“配合物1”:50% PEG400および50%水(v/v)の溶液中で200mg/mL(20% w/v)の濃度で溶解させた実施例1のパモ酸塩。
(3)“配合物3”:50% PEG400および50% PBS(v/v)の溶液中で300mg/mL(30% w/v)の濃度で溶解させた実施例1のパモ酸塩。
(5)“配合物5”:生理食塩水/2%熱非働化マウス血清/5% DMA/2% tween−80溶液中で溶解させた実施例1の酢酸塩。
配合物1および2に関して、Sprague−Dawleyラットに5μL/ラットもしくは1.0mg/ラットのどちらかの固定された量、または2.5mg/kg体重の変動可能な量で皮下注射により投与した。
試料の調製
配合物1および2に関して、100μLの血漿を5μLのギ酸で酸性化し、300μLのアセトニトリルで沈殿させた。その上清を遠心分離により集め、speed−vacにより乾燥させた。その乾燥したペレットを100μLの水中で溶解させ、次いでそれを遠心分離した。その調製物の50μLを、LC−MS/MS分析のために注入した。
配合物1および2に関して、Turbo Ionsprayプローブを備えたAPI4000質量分析システムを用いてLC−MS/MS分析を実施した。559.5および110.1のイオン対での分子イオン検出のMRMモードを用いた。HPLC分離を、Luna C8(2) 2×30mm 3μカラムで、0.3mL/分の流速において10分間で0%Bから80%Bまで動かして実施した。緩衝液Aは水中1%ギ酸であり、緩衝液Bはアセトニトリル中1%ギ酸である。LOQは5ng/mLであった。
配合物1〜5で投与された実施例1の血漿濃度をその標準的なキャリブレーションプロットを用いて計算し、その結果を表5に示す。
配合物3の薬物動態プロフィールの完全な時間経過プロットを、図3Aにおいて通常の目盛りで、そして図3Bにおいて対数目盛りで示す。
配合物5の薬物動態プロフィールの完全な時間経過プロットを、図5Aにおいて通常の目盛りで、そして図5Bにおいて対数目盛りで示す。
Claims (26)
- 1以上のメラノコルチン受容体のリガンドとして作用するペプチドを含む溶液の医薬組成物。であって、前記のペプチドが以下のもの:
Ac-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;
Ac-D-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;
Ac-Tyr-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;
Ac-Tyr-D-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;または
ヒダントイン(Arg-Gly)-シクロ(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2;
またはその医薬的に許容できる塩であり、
前記ペプチドが対象への皮下または筋肉内投与の後デポーを形成し、
前記デポーがゆっくりと溶解してペプチドを体液および血流中に放出し、
前記溶液は、有機性PEG200またはPEG400構成要素を有する水溶液であり、ここでPEGの水に対する体積対体積比が1:99から99:1までである、
前記医薬組成物。 - 前記のペプチドがAc-Arg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2である、請求項1に記載の医薬組成物。
- 前記の医薬的に許容できる塩がパモ酸塩である、請求項1または2に記載の医薬組成物。
- さらに第2の有機性構成要素を含み、有機性構成要素がアルコール、DMSO、DMF、またはDMAである請求項1〜3のいずれかに記載の医薬組成物。
- 前記のペプチドをPEG200またはPEG400水溶液中で溶解させ、ここでPEGの水に対する体積対体積比が約1:9から約1:1までである、請求項1〜4のいずれかに記載の医薬組成物。
- 前記のアルコールがエタノールまたはイソプロピルアルコールである、請求項4に記載の医薬組成物。
- 前記のペプチドの重量対体積濃度が約0.1mg/mL〜約600mg/mLである、請求項1〜6のいずれかに記載の医薬組成物。
- 前記の組成物のpHが約3.0〜約8.0である、請求項1〜7のいずれかに記載の医薬組成物。
- 前記のArg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2のパモ酸塩をPEG400/水溶液中で溶解させ、ここでPEG400の水に対する体積対体積比が約1:1であり、そのペプチドの重量対体積濃度が約200mg/mLである、請求項8に記載の医薬組成物。
- 前記のArg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2のパモ酸塩をPEG200/水溶液中で溶解させ、ここでPEG200の水に対する体積対体積比が約1:1であり、そのペプチドの重量対体積濃度が約200mg/mLである、請求項8に記載の医薬組成物。
- 前記のArg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2のパモ酸塩をPEG400/PBS溶液中で溶解させ、ここでPEG400のPBSに対する体積対体積比が約1:1であり、そのペプチドの重量対体積濃度が約300mg/mLである、請求項8に記載の医薬組成物。
- 前記のArg-シクロ(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2のパモ酸塩をPEG400/生理食塩水溶液中で溶解させ、ここでPEG400の生理食塩水溶液に対する体積対体積比が約1:1であり、そのペプチドの重量対体積濃度が約300mg/mLである、請求項8に記載の医薬組成物。
- さらに保存剤を含む、請求項1〜12のいずれかに記載の医薬組成物。
- 前記の保存剤が、m−クレゾール、フェノール、ベンジルアルコール、およびメチルパラベンからなるグループから選択される、請求項13に記載の医薬組成物。
- 前記の保存剤が約0.01mg/mLから約100mg/mLまでの濃度で存在する、請求項14に記載の医薬組成物。
- さらに等張剤を含む、請求項1〜15のいずれかに記載の医薬組成物。
- 前記の等張剤が約0.01mg/mLから約100mg/mLまでの濃度で存在する、請求項16に記載の医薬組成物。
- さらに安定剤を含む、請求項1〜17のいずれかに記載の医薬組成物。
- 前記の安定剤がイミダゾール、アルギニンおよびヒスチジンからなるグループから選択される、請求項18に記載の医薬組成物。
- さらに界面活性剤を含む、請求項1〜19のいずれかに記載の医薬組成物。
- さらにキレート剤を含む、請求項1〜20のいずれかに記載の医薬組成物。
- さらに緩衝剤を含む、請求項1〜21のいずれかに記載の医薬組成物。
- 前記の緩衝剤がトリス、酢酸アンモニウム、酢酸ナトリウム、グリシン、アスパラギン酸、およびビス−トリスからなるグループから選択される、請求項22に記載の医薬組成物。
- さらに二価金属を含む、請求項1〜23のいずれかに記載の医薬組成物。
- 前記の二価金属が亜鉛である、請求項24に記載の医薬組成物。
- 前記の溶液が透明な液体である、請求項1〜25のいずれかに記載の医薬組成物。
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Application Number | Priority Date | Filing Date | Title |
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US28136009P | 2009-11-16 | 2009-11-16 | |
US61/281,360 | 2009-11-16 | ||
PCT/US2010/056690 WO2011060352A1 (en) | 2009-11-16 | 2010-11-15 | Pharmaceutical compositions of melanocortin receptor ligands |
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US20120226018A1 (en) * | 2009-11-16 | 2012-09-06 | Ipsen Pharma, S.A.S. | Process for the Synthesis of Ac-Arg-Cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 |
BR112013027222B1 (pt) * | 2011-06-14 | 2022-07-12 | Ipsen Pharma S.A.S. | Composição de liberação sustentada que contém peptídeos como ingrediente ativo |
HUE056948T2 (hu) | 2011-12-29 | 2022-04-28 | Rhythm Pharmaceuticals Inc | Melanokortin-4 receptorral összefüggõ rendellenességek kezelési módszere heterozigóta hordozókban |
EP2705835A1 (en) * | 2012-06-08 | 2014-03-12 | Ipsen Pharma S.A.S. | Aqueous gelling compositions of soluble active pharmaceutical peptides providing modified release |
SG11201502949QA (en) * | 2012-11-05 | 2015-06-29 | Palatin Technologies Inc | Bremelanotide therapy for female sexual dysfunction |
JP6622690B2 (ja) | 2013-03-15 | 2019-12-18 | リズム・ファーマシューティカルズ・インコーポレイテッド | ペプチド組成物 |
PT2970389T (pt) | 2013-03-15 | 2020-10-21 | Rhythm Pharmaceuticals Inc | Composições farmacêuticas |
JP7051106B2 (ja) | 2015-09-30 | 2022-04-11 | リズム ファーマシューティカルズ, インコーポレイテッド | メラノコルチン-4受容体経路関連障害の治療方法 |
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