JP6802019B2 - インスリン分泌促進性ペプチドの懸濁製剤及び使用 - Google Patents
インスリン分泌促進性ペプチドの懸濁製剤及び使用 Download PDFInfo
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- JP6802019B2 JP6802019B2 JP2016187105A JP2016187105A JP6802019B2 JP 6802019 B2 JP6802019 B2 JP 6802019B2 JP 2016187105 A JP2016187105 A JP 2016187105A JP 2016187105 A JP2016187105 A JP 2016187105A JP 6802019 B2 JP6802019 B2 JP 6802019B2
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Description
本出願は、2007年4月23日に出願された米国仮出願第60/926,005号、及び2008年5月28日に出願された米国仮出願第61/072,202号の利益を主張し、これらの出願は本明細書中で、それらの全てが参照により援用される。
本発明は、医薬研究開発に応用される、有機化学、製剤化学、及びペプチド化学に関する。本発明の側面は、哺乳類における使用のための、及び疾患又は病態の処置のための、インスリン分泌促進性ペプチドの懸濁製剤を提供する。
グルカゴン様ペプチド-1(GLP-1)は、重要なホルモンの1つであり、そしてヒトプログルカゴン分子のフラグメントである。GLP-1は、ペプチダーゼ(ジペプチジルペプチダーゼIV又はDPP-IV)により急速に代謝される。GLP-1のフラグメントであるグルカゴン様ペプチド-1(7-36)アミド(グルカゴン様インスリン分泌促進性ペプチド、又はGLIP)は、生理的濃度でインスリンの放出を促進する胃腸ペプチドである(Gutniak M., et al., N Engl J Med. 1992 May 14;326(20):1316-22)。GLP-1及びGLP-1(7-36)アミドは、インクレチンである。インクレチンは、食後にベータ細胞から放出されるインスリンの量の増大を引き起こす胃腸ホルモンである。
本発明は、粒子製剤及び懸濁ビヒクルを含む懸濁製剤組成物、並びにそのような製剤を含む装置、そのような製剤及び装置を作製する方法、並びにそれらを使用する方法に関する。
本明細書中に引用される全ての特許、刊行物、及び特許出願は、各々個別の特許、刊行物、又は特許出願が、本明細書の全てにおいてあらゆる目的で参照により援用されることを特異的にかつ個別に示したが如く、本明細書中で参照により援用される。
本明細書中で使用される専門用語は唯特定の態様を記載することのみを目的とし、そして限定を意図するものではないことが理解されるべきである。本明細書及び添付された特許請求の範囲において使用されるとき、単数形の「ある(a)」、「ある(an)」及び「その(the)」は、文脈中に明確な別段の指示が無い限り、複数の対象を含む。故に、例えば、「ある溶媒」の参照は、2つ以上のそのような溶媒の組合せを含み、「あるペプチド」の参照は、1つ以上のペプチド、複数のペプチドの混合物等を含む。
[式中、
F/A=せん断応力(単位面積当たりの力)
μ=比例定数(粘性)
V/L=層の厚さあたりの速度(せん断速度)]
本発明を詳細に記載する前に、本発明は、特定の種類の薬物送達、特定の種類の薬物送達装置、特定のペプチドの供給源、特定の溶媒、特定のポリマー等に限定されないことを理解されたい。なぜなら、そのような特定の物の使用は、本発明の教示を考慮して選択され得るからである。また、本明細書中で使用される技術は、本発明の特定の態様を記載することのみを目的とし、限定を意図しないことも理解されたい。
2.1.1 粒子製剤
一の態様において、本発明は、例えばGLP-1又はエクセナチド等のインスリン分泌促進ペプチドの懸濁製剤を含む医薬組成物を提供する。上記懸濁組成物は、少なくとも1つのポリマー及び少なくとも1つの溶媒を含む、非水性単相ビヒクルを含む。前記ビヒクルは、好ましくは、粘性流体特性を呈する。前記ペプチド成分は、前記ビヒクル中に分散した粒子製剤中に前記インスリン分泌促進ペプチドを含む。典型的には、前記粒子製剤は、糖質、抗酸化剤、アミノ酸、緩衝剤、及び無機化合物からなる群から選択される1つ以上の安定化剤成分を含む安定化成分を含む。
本発明の一の側面において、前記懸濁ビヒクルは、インスリン分泌促進性ペプチド粒子製剤がその中で分散する安定な環境を提供する。前記粒子製剤は、前記懸濁ビヒクル中で化学的及び物理的に安定(上記と同じ)である。前記懸濁ビヒクルは、インスリン分泌促進性ペプチドを含む粒子が均一に懸濁するのに十分な粘性を有する溶液を形成する1つ以上のポリマー及び1つ以上のビヒクルを典型的に含む。
本明細書中に記載される懸濁製剤は、数週、数ヶ月、又は約1年に渡る長期間、化合物の持続的な送達を提供するために、移植可能な薬物送達装置に使用され得る。そのような移植可能な薬物送達装置は、典型的には、所望の期間にかけて所望の流量で化合物の送達を可能とする。前記懸濁製剤は、通常の技術により、その移植可能な薬物送達装置に充填される。
本明細書中に記載される懸濁製剤は、糖尿病の対象におけるインスリン療法の有望な代替手段を提供する。糖尿病タイプ2又は2型糖尿病(インスリン非依存性糖尿病(NIDDM))は、インスリン耐性、相対的なインスリン欠乏、及び高血糖により原始的に特徴付けられる代謝疾患である。インスリン分泌促進性ペプチドを含む本発明に係る懸濁製剤は、インスリン分泌の刺激、グルカゴン分泌の抑制、胃内容排出の遅延、及び場合によっては筋及び脂肪等の末梢組織におけるインスリン感受性の亢進において有用である。
以下の実施例は、当業者に対し、本発明に係る装置、方法、及び製剤を製造及び使用する方法の完全な開示及び記載を提供するように提示されるものであり、発明者が発明とみなすものの範囲を限定することを意図しない。使用される数値(例えば量、温度等)に関しては正確を期するよう努めているが、ある程度の実験的錯誤及び偏差が含まれ得る。示唆されていない限り、部とは重量部であり、分子量は平均分子量であり、温度はセルシウス度であり、そして圧力は大気圧又はその付近である。
エクセナチド粒子製剤
この実施例は、エクセナチド粒子製剤の作製を記載する。
エクセナチド(0.25g)は、pH6.04の50mMクエン酸ナトリウム緩衝液中に溶解された。前記溶液は、クエン酸ナトリウム、スクロース、及びメチオニンを含む製剤溶液で透析された。そして前記製剤化溶液は、0.7mmノズルを備え、出口温度が75℃であり、気化圧力が100Psiであり、固体含有率が2%であり、そして流速が2.8mL/minであるBuchi290を使用して噴霧乾燥された。前記乾燥粉末は、21.5%のエクセナチドと4.7%の残留水分を含み、密度は0.228g/mlであった。
2つの追加的なエクセナチドの製剤が、本質的に先述の方法により調製された。以下の表3において、前記製剤1、2、及び3の構成成分の重量パーセント(wt%)がまとめられている。
GLP-1乾燥粉末
この実施例は、GLP-1(7-36)アミド粒子製剤の作製を記載する。
GLP-1(7-36)アミド(1.5g)は、pH4の5mMクエン酸ナトリウム緩衝液中に溶解された。前記溶液は、クエン酸ナトリウム緩衝剤及びメチオニンを含む製剤溶液で透析された。そして前記製剤化溶液は、0.7mmノズルを備え、出口温度が70℃であり、気化圧力が100Psiであり、固体含有率が1.5%であり、そして流速が5mL/minであるBuchi290を使用して噴霧乾燥された。前記乾燥粉末は、90%のGLP-1(7-36)アミドを含んでいた。
エクセナチド懸濁製剤
この実施例は、懸濁ビヒクル及びエクセナチド粒子製剤を含む懸濁製剤の作製を記載する。
エクセナチド粒子製剤は噴霧乾燥により製造され、そして20wt%のエクセナチド、32wt%のスクロース、16wt%のメチオニン、及び32wt%のクエン酸緩衝剤を含んでいた。
懸濁ビヒクルは、乾燥大気中で、及び減圧下で、ポリビニルピロリドンK-17(典型的には、平均分子量が約7,900〜10,800の範囲にある)ポリマーを、約65℃まで加熱した安息香酸ベンジル溶媒中に、約50/50の重量比率で溶解することにより形成された。前記ビヒクルの粘性は、33℃で測定されたとき、約12,000〜18,000ポアズであった。実施例1に記載の粒子製剤1〜3は、表4に示される濃度(重量パーセント)で、前記ビヒクル全体に分散した。
GLP-1(7-36)アミド製剤
この実施例は、懸濁ビヒクル及びGLP-1(7-36)アミド粒子製剤を含む懸濁製剤の作製を記載する。GLP-1(7-36)アミド粒子製剤は、噴霧乾燥により製造され、そして90wt%のGLP-1、5wt%のメチオニン、及び5wt%のクエン酸緩衝液を含んでいた。
DUROS(登録商標)装置を使用したエクセナチドの持続的送達による処置動物におけるグルコースレベルの低下及び体重減少
この実施例におけるデータは、DUROS(登録商標)装置からのエクセナチド製剤の持続的かつ構成的な送達の、2型糖尿病のZucker Diabetic Fatty(ZDF)ラットモデルにおけるグルコースレベル及び体重に対する影響を示した。
Claims (18)
- 粒子製剤と非水性単相懸濁ビヒクルとを含む懸濁製剤であって、
前記粒子製剤は、インスリン分泌促進性ペプチド、抗酸化剤、及び緩衝剤を含み、
前記インスリン分泌促進性ペプチドはエクセナチドであり、前記抗酸化剤はメチオニンであり、
前記非水性単相懸濁ビヒクルが、20重量%〜60重量%の溶媒と、80重量%〜40重量%のピロリドンポリマーとを含み、
前記溶媒は、乳酸ラウリル、ラウリルアルコール、及び安息香酸ベンジルのうち少なくとも1つであり、
前記粒子製剤の30重量%〜90重量%が前記インスリン分泌促進性ペプチドであり、
前記粒子製剤におけるインスリン分泌促進性ペプチドの抗酸化剤に対する比率は、2.5/1〜10/1であり、
前記懸濁ビヒクルの粘度が、37℃で5,000ポアズ〜50,000ポアズであり、
前記粒子製剤は前記ビヒクル中に懸濁されてなり、
浸透圧送達装置と組み合わせて使用され;
当該浸透圧送達装置が:
前記懸濁製剤と浸透圧エンジンとを含む管腔を有する容器;
前記管腔内に配置されて、前記懸濁製剤を前記浸透圧エンジンから隔離するピストン部品;
前記浸透圧エンジンと隣接する前記容器の第一の遠位端に配置される半透膜;及び
前記懸濁製剤と隣接する前記容器の第二の遠位端に配置される流量変調器;
を備える、懸濁製剤。 - 前記緩衝剤が、クエン酸塩、ヒスチジン、コハク酸塩、及びトリスのうち少なくとも1つから選択される、請求項1に記載の懸濁製剤。
- 前記緩衝剤が、クエン酸塩である、請求項1に記載の懸濁製剤。
- 糖質を更に含む、請求項1〜3の何れか一項に記載の懸濁製剤。
- 前記糖質が、ラクトース、スクロース、トレハロース、セロビオース、及びラフィノースのうち少なくとも1つである、請求項4に記載の懸濁製剤。
- 前記糖質がスクロースである、請求項5に記載の懸濁製剤。
- 前記粒子製剤が、エクセナチド、スクロース、メチオニン、及びクエン酸を含む、請求項6に記載の懸濁製剤。
- 前記溶媒が、安息香酸ベンジルである、請求項1〜7の何れか一項に記載の懸濁製剤。
- ピロリドンポリマーが、ポリビニルピロリドンである、請求項1〜8の何れか一項に記載の懸濁製剤。
- 前記粒子製剤におけるインスリン分泌促進性ペプチドの抗酸化剤に対する比率が、5/1〜10/1である、請求項1〜9の何れか一項に記載の懸濁製剤。
- 前記粒子製剤の粒子径が3μm〜50μmである、請求項1〜10の何れか一項に記載の懸濁製剤。
- 前記粒子製剤が、少なくとも1ヶ月〜少なくとも1年に亘って、送達温度37℃〜40℃において、化学的及び物理的に安定である、請求項1〜11の何れか一項に記載の懸濁
製剤。 - 前記粒子製剤の水分含量が5重量%未満である、請求項1〜12の何れか一項に記載の懸濁製剤。
- 請求項1〜13の何れか一項に記載の懸濁製剤を含む、浸透圧送達装置であって、当該浸透圧送達装置が:
前記懸濁製剤と浸透圧エンジンとを含む管腔を有する容器;
前記管腔内に配置されて、前記懸濁製剤を前記浸透圧エンジンから隔離するピストン部品;
前記浸透圧エンジンと隣接する前記容器の第一の遠位端に配置される半透膜;及び
前記懸濁製剤と隣接する前記容器の第二の遠位端に配置される流量変調器;
を備える、浸透圧送達装置。 - 対象におけるII型糖尿病の治療に使用される、請求項1〜13の何れか一項に記載の懸濁製剤。
- 対象における体重の低減に使用される、請求項1〜13の何れか一項に記載の懸濁製剤。
- 対象における血中グルコース濃度の低減に使用される、請求項1〜13の何れか一項に記載の懸濁製剤。
- 対象におけるHbA1Cレベルの低減に使用される、請求項1〜13の何れか一項に記載の懸濁製剤。
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