JP5198261B2 - Glp−1類似体製剤 - Google Patents
Glp−1類似体製剤 Download PDFInfo
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- JP5198261B2 JP5198261B2 JP2008515284A JP2008515284A JP5198261B2 JP 5198261 B2 JP5198261 B2 JP 5198261B2 JP 2008515284 A JP2008515284 A JP 2008515284A JP 2008515284 A JP2008515284 A JP 2008515284A JP 5198261 B2 JP5198261 B2 JP 5198261B2
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- 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
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Description
His7−Ala−Glu−Gly10−Thr−Phe−Thr−Ser−Asp15−Val−Ser−Ser−Tyr−Leu20−Glu−Gly−Gln−Ala−Ala25−Lys−Glu−Phe−Ile−Ala30−Trp−Leu−Val−Lys−Gly−Arg−Gly37
未変性(ヒト):
GLP−1(7−36)アミド
ノボノルディスク(NovoNordisk)(リラグルチド)
Arg34Lys26−(N−ε−γ−Glu(N−α−ヘキサデカノイル)))−GLP−1(7−37)
コンジュケム(Conjuchem)(CJC−1131)
D−Ala8Lys37−(2−(2−(2−マレイミドプロピオンアミド(エトキシ)エトキシ)アセトアミド))−GLP−1(7−37)
サノフィ−アベンティス/ジーランド(Sanofi−Aventis/Zealand)(AVE−010(ZP10)
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Leu−Ser−Lys−Gln−Met−Glu−Glu−Glu−Ala−Val−Arg−Leu−Phe−Ile−Glu−Trp−Leu−Lys−Asn−Gly−Gly−Pro−Ser−Ser−Gly−Ala−Pro−Pro−Ser−Lys−Lys−Lys−Lys−Lys−Lys
イーライ リリー(Eli Lilly)(エクセナチド)
His7−Gly−Glu−Gly10−Thr−Phe−Thr−Ser−Asp15−Leu−Ser−Lys−Gln−Met20−Glu−Glu−Glu−Ala−Val25−Arg−Leu−Phe−Ile−Glu30−Trp−Leu−Lys−Asn−Gly−Gly−Pro37−Ser−Ser−Gly−Ala−Pro−Pro−Pro−Ser
本明細書中で使用される「未変性GLP−1」とは、ヒトGLP−1(7−37)および/またはヒトGLP−1(7−36)アミドを示し、「リラグルチド」、「CJC−1131」、「AVE−010」、および「エクセナチド」という用語は上記のそれぞれの活性体を示すのに使用されており、これら活性体は、文脈から読み取れる場合、それらの生理学的に許容できる塩、エステルおよび誘導体を含む。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と
の低粘度混合物を含む前製剤であって、
水性流体と接触すると、少なくとも1種の液晶相構造を形成するか、または形成することができる前製剤を提供する。
a)少なくとも1種のジアシルグリセロールと、
b)少なくとも1種のホスファチジルコリンと、
c)少なくとも1種の酸素含有有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
の低粘度混合物を含むであろう前製剤であって、
水性流体と接触すると、少なくとも1種の液晶相構造を形成するか、または形成することができる。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
の低粘度混合物を含む前製剤を、腸管外的に(例えば、筋肉内注射または、好ましくは、皮下注射で)投与することを含み、
この方法によって、投与後に、水性流体にインビボで接触すると少なくとも1種の液晶相構造が形成される。好ましくは、そのような方法で投与される前記前製剤は、本明細書中に記載の本発明の前製剤である。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
の低粘度混合物を含む前製剤を、水性流体にインビボで曝露することを含む液晶デポー組成物を調製するための方法も提供する。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
の低粘度混合物を形成することと、
少なくとも1種のGLP−1類似体を、前記低粘度混合物、または前記低粘度混合物を形成する前に成分a、bまたはcのうちの少なくとも1つに溶解または分散させることとを含むプロセスを提供する。好ましくは、そのように形成された前記前製剤は、本明細書中に記載の本発明の製剤である。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
の低粘度混合物の、当該GLP−1類似体の持続的な投与に使用される前製剤の製造における使用であって、当該前製剤が、水性流体と接触すると、少なくとも1種の液晶相構造を形成することができる低粘度混合物の使用を提供する。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
の低粘度混合物を含む前製剤を投与することを含む方法を提供する。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは、酸素含有の)有機溶媒と、
d)少なくとも1種のGLP−1類似体と、
のタイプI糖尿病、タイプII糖尿病、過剰体重および/または肥満を治療するためのデポーのインビボでの形成において使用される低粘度前製剤医薬品の製造における使用を提供する。
a)少なくとも1種のジアシルグリセロールおよび/または少なくとも1種のトコフェロール、
b)少なくとも1種のホスファチジルコリン、
c)少なくとも1種の酸素含有有機溶媒、
である。
i)本明細書中に記載の成分a)からc)の低粘度混合物を含む第1容器と、
ii)少なくとも1種のGLP−1類似体を含む第2容器と、
iii)任意的に、かつ好ましくは、
1)(当該第1および第2容器の1つまたは両方であってもよい)少なくとも1つの注射器と、
2)本明細書中に記載のもののような投与用針と、
3)前記第1および第2容器の内容物から本発明の組成物を生成することに関する説明書と、
4)本明細書中に記載のデポーを形成するための、投与に関する説明書
のうちの少なくとも1つとを
含む2成分キットを提供する。
はI2相を含む混合相を形成してもよい。I2相は、不連続な水性領域を有する逆キュービック液晶相である。この相は、活性物質の制御放出に特に有利であり、とりわけ水溶性活性体等の極性活性物質と組み合わせた場合に特に有利である。これは、不連続な極性ドメインが、前記活性体の迅速な拡散を防止するからである。L2におけるデポー前駆体は、I2相デポー構成物との併用が極めて効果的である。これは、L2相が、分離した極性コアを取り囲む連続的な疎水性領域を有するいわゆる「逆ミセル」相であるからである。よって、L2は、親水性の活性体と同様の利点を有する。
成分a)は、GDOを含むか、実質的にGDOで構成されるか、または好ましくはGDOで構成される;
成分b)は、大豆PCを含むか、実質的に大豆PCで構成されるか、または好ましくは大豆PCで構成される;
成分c)は、1、2、3もしくは4炭素アルコール、好ましくはイソプロパノール、またはより好ましくはエタノールを含むか、実質的にこのような成分で構成されるか、または好ましくはこのような成分で構成される;
前記前製剤は、本明細書中に示すものから選択される少なくとも1種のGLP−1類似体、好ましくはGLP−1(7−37)、GLP−1(7−36)アミド、リラグルチド、AVE−010、TH−0318またはエクセナチドを含有する;
前記前製剤は、本明細書中に示す低粘度を有する。
前記方法は、先に示した好ましい特徴を1つ以上有する少なくとも1種の製剤を投与することを含む;
前記方法は、本明細書中に示す少なくとも1種の製剤を、筋肉内注射、皮下注射、または好ましくは深部皮下注射によって投与することを含む;
前記方法は、本明細書中に示す充填済み投与デバイスを用いて投与することを含む;
前記方法は、20ゲージ以下、好ましくは20ゲージ未満、および最も好ましくは23ゲージ以下の針を通して投与することを含む;
前記方法は、7から360日ごと、好ましくは7から120日ごと、より好ましくは14から60日ごとに1回投与することを含む。
前記使用は、先に示した好ましい特徴を1つ以上有する少なくとも1種の製剤の使用を含む;
前記使用は、本明細書中に示す少なくとも1種の製剤を、筋肉内注射、皮下注射、または好ましくは深部皮下注射によって投与するための医薬品の製造を含む;
前記使用は、本明細書中に示す充填済み投与デバイスを用いて投与するための医薬品の製造を含む;
前記使用は、20ゲージ以下、好ましくは20ゲージ未満、および最も好ましくは23ゲージ以下の針を通して投与するための医薬品の製造を含む;
前記使用は、7から360日ごと、好ましくは7から120日ごと、より好ましくは14から60日ごとに1回投与するための医薬品の製造を含む。
前記充填済みデバイスは、本明細書中に示す好ましい製剤を含有する;
前記充填済みデバイスは、20ゲージ未満、好ましくは23ゲージ以下の針を含む;
前記充填済みデバイスは、1回分の用量である0.05から250mg、好ましくは0.1から100mgおよびより好ましくは1〜50mgのGLP−1類似体を含む;
前記充填済みデバイスは、GLP−1(7−37)、GLP−1(7−36)アミド、TH−0318、リラグルチドまたはAVE−010を、0.05から250mg前後含む;
前記充填済みデバイスは、本発明の組成物の均質な混合物を注射準備完了形態で含む。
前記キットは、本明細書中に示す好ましい製剤を含む;
前記キットは、本明細書中に示す充填済みデバイスを含む;
前記キットは、20ゲージ未満、好ましくは23ゲージ以下の針を含む;
前記キットは、1回分の用量である0.05から250mg、好ましくは0.1から100mgおよびより好ましくは1〜50mgのGLP−1類似体を含む;
前記キットは、GLP−1(7−37)、GLP−1(7−36)アミド、TH−0318、リラグルチドまたはAVE−010を、0.05から250mg前後含む;
前記キットは、本発明の脂質製剤とGLP−1類似体粉末をそれぞれ含む少なくとも2つの容器を含む「二区画キット」を含む。
前記キットは、本明細書中に記載の治療方法において使用する投与に関する説明書を含む。
実施例
使用される略語
GLP−1=GLP−1(7−36)アミド(酢酸塩)=グルカゴン様ペプチド1(ポリペプチド ラボラトリーズ(PolyPeptide Laboratories)、ドイツ)
SPC=大豆ホスファチジルコリン(リポイド(Lipoid)、ドイツ)
EPC=卵ホスファチジルコリン(リポイド、ドイツ)
GDO=グリセロールジオレアート(ダニスコ(Danisco)、デンマーク)
P80=ポリソルベート(Polysorbate)80(アポテケット(Apoteket)、スウェーデン)
F68=プルロニック(Pluronic)F68(シグマ−アルドリッチ(Sigma−Aldrich)、スウェーデン)
EtOH=エタノール(ケメチル(Kemetyl)、スウェーデン)
HAc=酢酸(メルク(Merck)、ドイツ)
BzOH=ベンジルアルコール(アポテケット、スウェーデン)
PG=プロピレングリコール(アポテケット、スウェーデン)
BzB=安息香酸ベンジル(アポテケット、スウェーデン)
NMP=N−メチルピロリドン(ISP、米国)
アスコルビン酸=Asc(シグマ−アルドリッチ、スウェーデン)
EDTA=エチレンジアミン四酢酸(シグマ−アルドリッチ、スウェーデン)
DPP−IV=ジペプチジルペプチダーゼIV
DOPG=ジオレオイルホスファチジルグリセロール(アバンティポーラーリピッズ(Avanti Polar Lipids)、米国)
ホスファチジルコリン(「PC」−リポイド(Lipoid)S100)とグリセロールジオレアート(GDO)を異なる割合で含有し、更にEtOHを溶媒として含有する注射可能製剤を調製し、デポー前駆体製剤を過剰量の水で平衡化した後、各種液晶相が得られることを例証した。
PC/GDOと共溶媒の混合物を、実施例1の方法で調製した。まずロータリーエバポレーターを用いて前記PC/GDO混合物からEtOHを蒸発させることによって、EtOH含有量を調整し、実質的にPCおよびGDOからなる粘性液体混合物を得た。その後、共溶媒を、下記表2に示す割合で添加した。
各種容量(1、2、6ml/kg)のデポー前駆体(PCが36%wt、GDOが54%wt、およびEtOHが10%wt)をラットに注射し、14日間後に再び除去した。この後、相当量の製剤が依然としてラットの皮下に存在したことが分かった。表3参照。
GLP−1のデポー前駆体を以下の2つの異なる方法で調製した。
1)GLP−1を、まずPC、GDOおよびEtOHと、混合が容易になるようにEtOHを過剰添加して混合した。典型的に、この段階でのEtOH含有量は、約50〜80wt%であった。次いで、過剰量のEtOHを、ロータリーエバポレーターまたは凍結乾燥により除去し、EtOHの最終含有量を、その後、必要に応じて調整した。
2)GLP−1を、まず少量の無菌水に溶解させた。その後、予め作製しておいたPC,GDOおよびEtOHの、EtOH含有量を約5〜10重量%とした液体混合物をGLP−1/水の溶液に添加した。得られた混合物をボルテックス混合で1分間混合した。
SPC(1.44g)、GDO(1.44g)、P80(0.72g)およびEtOH(0.40g)をガラスバイアルに順に加え、その後、24時間転倒型回転を行って、液体保存溶液を調製した。透明で均質な液体脂質保存溶液を得た。
5.2 脂質/GLP−1製剤の調製
20mgのGLP−1(酢酸塩)をバイアルで計量し、HAcを2wt%含有する水溶液0.352gを添加して溶解させ、その後、ボルテックス混合を行った。GLP−1の保存水溶液に、5.1で調製した脂質保存溶液1.628gを添加した。得られた製剤を、短時間のボルテックス混合後、1時間の転倒型回転を行って混合し、透明で均質な低粘度脂質/GLP−1製剤を得た。
研究の第1日目に、ラット(スプレーグ−ドーリー(Sprague−Dawley)の雄ラット)を計量し、標準的な手順に従って静脈カテーテルを挿入することによる実験用に準備した。簡潔に言えば、これらのラットを、エンフルランおよびブプレノルフィン(Buprinorphin)を用いて麻酔した。シリコンカテーテルを、頸静脈内に挿入し、固定し、皮膚の下を通して、血液のサンプリングのために外在化させた頸部背側部まで貫通させた。これらラットは、投薬前に48時間の回復期間が与えられた。
13.2 サンプリング
投薬前、投薬後1時間、3時間、6時間、1日、2日、7日、14日、21日および28日後に、血液試料を採取した。血液0.4mLの血液試料を、氷で冷やしたEDTA処理済試験管に採取した。これら試験管に、市販のDPP−IV阻害剤を加えた。各サンプリング後、注射用無菌0.9%NaCl(10mM EDTAを含む)を、カテーテルを通してラットに与えて喪失した血液量を補った。
13.3 生物分析
分析前に、これら試料を−80℃未満で保存した。EDTA血漿試料におけるGLP−1濃度を、市販のエリザ(ELISA)(グルカゴン様ペプチド1(活性)エリザキット(ELISA Kit)、Cat.#EGLP−35K、リンコリサーチ(Linco Research)により測定した。
13.4結果
図1は、PKプロファイルを示す。28日間で、GLP−1血漿中レベルが、プラセボと比較して著しく上昇したことが分かる。両製剤に関して、放出の遅延相が存在せず、注射後2日以内に、安定したプラトー血漿中GLP−1レベルが達成されたことは重要なことである。GLP−1デポー製剤の持続期間は、非常に短期間であるペプチドの血漿中半減期(5分未満)を考慮すると、際立ってすばらしい。
Claims (23)
- a)グリセロールジオレアート(GDO)を含む少なくとも1種のジアシルグリセロールを33〜55重量%と、
b)33〜55重量%の少なくとも1種のホスファチジルコリンと、
c)エタノールを含む少なくとも1種の生体適合性の酸素含有有機溶媒と、
d)0.02〜12重量%の少なくとも1種のGLP−1類似体と、
の低粘度混合物であって、a:bの重量比が、40:60〜70:30の範囲であり、20℃における前記低粘度混合物の粘度が1〜1000mPaである低粘度混合物を含む前製剤であって、
水性流体と接触すると、少なくとも1種の液晶相構造を形成するか、または形成することができる前製剤。 - 前記少なくとも1種のホスファチジルコリンが、大豆ホスファチジルコリンを含む請求項1に記載の前製剤。
- 当該少なくとも1種のGLP−1類似体が、未変性GLP−1、リラグルチド(Liraglutide)、TH−038、エクセナチド(Exenatide)および/またはAVE−010から選択される請求項1または2に記載の前製剤。
- 当該前製剤が、付加的に、少なくとも1種のポリエチレンオキシド断片化剤を含む請求項1から3の何れかに記載の前製剤。
- タイプI糖尿病、タイプII糖尿病、過剰体重および肥満から選択される少なくとも1つの症状を治療するための請求項1から4の何れかに記載の前製剤。
- GLP−1類似体を用いて、治療を必要とする非ヒト哺乳類である対象に治療を行うための方法であって、当該方法は、当該対象に
a)グリセロールジオレアート(GDO)を含む少なくとも1種のジアシルグリセロールを33〜55重量%と、
b)33〜55重量%の少なくとも1種のホスファチジルコリンと、
c)エタノールを含む少なくとも1種の生体適合性の酸素含有有機溶媒と、
d)0.02〜12重量%の少なくとも1種のGLP−1類似体と、
の低粘度混合物であって、a:bの重量比が、40:60〜70:30の範囲であり、20℃における前記低粘度混合物の粘度が1〜1000mPaである低粘度混合物を含む前製剤を投与することを含む方法。 - 前記治療方法が、タイプI糖尿病、タイプII糖尿病、過剰体重および肥満から選択される少なくとも1つの症状を治療するための方法である請求項6に記載の方法。
- 請求項1から5の何れかに記載の少なくとも1種の前製剤を投与することを含む請求項6または7に記載の方法。
- 筋肉内注射または皮下注射によって投与することを含む請求項6から8の何れかに記載の方法。
- 充填済み投与デバイスを用いて投与することを含む請求項6から9の何れかに記載の方法。
- 20ゲージ未満の針を通して投与することを含む請求項6から10の何れかに記載の方法。
- 7から180日ごとに1回投与することを含む請求項6から11の何れかに記載の方法。
- 投与用量が送達時点において選択される請求項6から12の何れかに記載の方法。
- 前記選択された用量が、前記対象の体重を基準として選択される請求項13に記載の方法。
- 前記投与用量が、注射容量によって選択される請求項13または14に記載の方法。
- a)グリセロールジオレアート(GDO)を含む少なくとも1種のジアシルグリセロールを33〜55重量%と、
b)33〜55重量%の少なくとも1種のホスファチジルコリンと、
c)エタノールを含む少なくとも1種の生体適合性の酸素含有有機溶媒と、
d)0.02〜12重量%の少なくとも1種のGLP−1類似体と、
の低粘度混合物であって、a:bの重量比が、40:60〜70:30の範囲であり、かつ、20℃における前記低粘度混合物の粘度が1〜1000mPaである低粘度混合物を含む前製剤の測定用量が予め装填された使い捨て投与デバイス。 - 1回分の用量である0.05から250mgのGLP−1類似体を含む請求項16に記載のデバイス。
- 前記少なくとも1種のホスファチジルコリンが、大豆ホスファチジルコリンを含む請求項16または17に記載のデバイス。
- 少なくとも1種類のGLP−1類似体を投与するためのキットであり、
a)グリセロールジオレアート(GDO)を含む少なくとも1種のジアシルグリセロールを33〜55重量%と、
b)33〜55重量%の少なくとも1種のホスファチジルコリンと、
c)エタノールを含む少なくとも1種の生体適合性の酸素含有有機溶媒と、
d)0.02〜12重量%の少なくとも1種のGLP−1類似体と、
の低粘度混合物であって、a:bの重量比が、40:60〜70:30の範囲であり、かつ、20℃における前記低粘度混合物の粘度が1〜1000mPaである低粘度混合物を含む製剤の測定用量を含むキット。 - 20ゲージ未満の針を更に含む請求項19に記載のキット。
- 1回分の用量である0.05から250mgのGLP−1類似体を含む請求項19または20に記載のキット。
- 前記少なくとも1種類のGLP−1類似体として、未変性GLP−1、リラグルチド、TH−0318、エクセナチドおよび/またはAVE−010を、0.05から250mg前後含む請求項19から21の何れかに記載のキット。
- 請求項1に記載の前製剤の形成のためのキットであり、
前記キットは、
i) a)グリセロールジオレアート(GDO)を含む少なくとも1種のジアシルグリセロールを33〜55重量%と、
b)33〜55重量%の少なくとも1種のホスファチジルコリンと、
c)エタノールを含む少なくとも1種の生体適合性の酸素含有有機溶媒と、
の低粘度混合物を含む第1容器と、
ii) 0.02〜12重量%の少なくとも1種のGLP−1類似体を含む第2容器と
を含む2成分キットであるキット。
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GBPCT/GB2005/004752 | 2005-12-09 | ||
PCT/GB2005/004752 WO2006075125A1 (en) | 2005-01-14 | 2005-12-09 | GnRH ANALOGUE FORMULATIONS |
PCT/GB2006/002079 WO2006131730A1 (en) | 2005-06-06 | 2006-06-06 | Glp-1 analogue formulations |
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EP1888031A1 (en) | 2008-02-20 |
US8546326B2 (en) | 2013-10-01 |
PL1888031T3 (pl) | 2013-04-30 |
CA2609810C (en) | 2012-05-22 |
JP2008542437A (ja) | 2008-11-27 |
ES2399645T3 (es) | 2013-04-02 |
EP1888031B1 (en) | 2013-01-23 |
CN101217940B (zh) | 2013-03-27 |
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