JP6709088B2 - ポリペプチドを含有する医薬組成物 - Google Patents
ポリペプチドを含有する医薬組成物 Download PDFInfo
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- JP6709088B2 JP6709088B2 JP2016053094A JP2016053094A JP6709088B2 JP 6709088 B2 JP6709088 B2 JP 6709088B2 JP 2016053094 A JP2016053094 A JP 2016053094A JP 2016053094 A JP2016053094 A JP 2016053094A JP 6709088 B2 JP6709088 B2 JP 6709088B2
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Description
特許文献1及び非特許文献1には、自己組織化ペプチドとしてAc−(Arg−Ala−Asp−Ala)4−CONH2(配列番号1)で表されるポリペプチドを使用した水溶性薬剤であるインスリンの徐放製剤が開示されている。また、非特許文献2には、Ac−(Arg−Ala−Asp−Ala)4−CONH2で表されるポリペプチドを用い、薬物としてピンドロール、キニン及びマレイン酸チモロールを包含した徐放製剤が開示されている。ここで、上記文献中、Ac−(Arg−Ala−Asp−Ala)4−CONH2で表されるポリペプチドは、PuraMatrix(登録商標)であるが、PuraMatrix(登録商標)は、Ac−(Arg−Ala−Asp−Ala)4−NH2とも表されることから、本明細書では、PuraMatrix(登録商標)をAc−(Arg−Ala−Asp−Ala)4−NH2と記載する(配列番号1)。
しかしながら、これら文献に記載の徐放製剤は、水のみが溶媒として使用されており、いずれの文献にも、薬物及びAc−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドを含有する医薬組成物の溶媒として、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される有機溶媒を使用することは記載されておらず、該医薬組成物が薬物の徐放製剤として有用であることも一切記載されていない。
〔1〕薬物と、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドと、有機溶媒とを含有する医薬組成物であって、
前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、医薬組成物。
〔2〕さらに、水を含有する、前記〔1〕記載の医薬組成物。
〔3〕前記有機溶媒と水の体積比が99:1〜60:40である、前記〔2〕記載の医薬組成物。
〔4〕前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールの平均分子量が90から2200の範囲内である、前記〔1〕〜〔3〕のいずれか一項に記載の医薬組成物。
〔5〕前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールがPEG400である、前記〔1〕〜〔3〕のいずれか一項に記載の医薬組成物。
〔6〕前記薬物の含有量が、0.01〜30%(w/v)である、前記〔1〕〜〔5〕のいずれか一項に記載の医薬組成物。
〔7〕前記Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドの含有量が、0.001〜5%(w/v)である、前記〔1〕〜〔6〕のいずれか一項に記載の医薬組成物。
〔8〕前記有機溶媒の含有量が70〜99.99%(w/w)である、前記〔1〕〜〔7〕のいずれか一項に記載の医薬組成物。
〔9〕薬物、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、ポリエチレングリコール、及び水のみから実質的になる、前記〔1〕〜〔8〕のいずれか一項に記載の医薬組成物。
〔10〕薬物、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、及びジメチルスルホキシドのみから実質的になる、前記〔1〕に記載の医薬組成物。
〔11〕薬物が、式(1):
[式中、
R1は水素原子、ハロゲン原子、ヒドロキシル基、C1-6アルキル基、1個若しくは複数個のハロゲン原子で置換されたC1-6アルキル基、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、;
R2は水素原子、C1-6アルキル基、C1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す]
で表される化合物又はその塩である、前記〔1〕〜〔10〕のいずれか一項に記載の医薬組成物。
〔12〕薬物が、2−[[[2−[(ヒドロキシアセチル)アミノ]−4−ピリジニル]メチル]チオ]−N−[4−(トリフルオロメトキシ)フェニル]−3−ピリジンカルボキサミド又はその塩である、前記〔1〕〜〔10〕のいずれか一項に記載の医薬組成物。
〔13〕眼疾患を予防又は治療するための、前記〔1〕〜〔12〕のいずれか一項に記載の医薬組成物。
〔14〕硝子体内又は前房内投与用である、前記〔13〕に記載の医薬組成物。
〔15〕薬物徐放用である、前記〔13〕又は〔14〕に記載の医薬組成物。
〔16〕Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドと、有機溶媒とを含有する薬物用徐放性付与剤であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、徐放性付与剤。
〔17〕薬物に、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド及び有機溶媒を添加する工程を含む、薬物に徐放性を付与する方法であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、方法。
本発明の徐放性付与剤は、薬物に良好な徐放性を付与するのに適している。
本発明の薬物に徐放性を付与する方法は、薬物に良好な徐放性を付与することができる。
<ポリペプチド>
本発明におけるポリペプチドは、Ac−(Arg−Ala−Asp−Ala)4−NH2(配列番号1)で表されるポリペプチド(以下、ポリペプチドAともいう)は、PuraMatrix(登録商標)として株式会社スリー・ディー・マトリックスより販売されている。C末端のカルボキシル基(COOH)はアミド化(CONH2)されている。
当該ポリペプチドAの含有量は、特に制限はないが、0.001〜5%(w/v)が好ましく、0.005〜3%(w/v)がより好ましく、0.01〜2%(w/v)がさらに好ましく、0.05〜1%(w/v)が特に好ましく、0.1〜0.5%(w/v)が最も好ましい。なお、「%(w/v)」は、本発明の医薬組成物100mL中に含まれる対象成分(ここでは、ポリペプチドA)の質量(g)を意味する。以下、特に断りがない限り同様とする。
本発明における薬物に特に制限はないが、疎水性薬物であることが好ましい。疎水性薬物とは、水に溶解しにくい薬物のことであり、疎水性の程度は分配係数CLogP等を指標にして表される。CLogPとは、化学物質の1−オクタノール/水系の分配係数の対数を計算により求めた値であり、その詳細は特開2009−298878号公報などに記載されている。本発明における薬物として、分配係数CLogPが0.5以上で規定される疎水性薬物が好ましく、CLogPが1以上20以下の薬物がより好ましく、1.5以上15以下の薬物がさらに好ましく、2以上12以下の薬物さらに好ましく、2.2以上9以下の化合物が特に好ましく、2.5以上8以下の化合物が最も好ましい。本発明における薬物の具体例としては、Tafetinib、SIM-817378、ACTB-1003、Chiauranib、CT-53608、Cinnamon、chim4G8-SDIE、CEP-5214、IMC-1C11、CEP-7055、3-[5-[2-[N-(2-Methoxyethyl)-N-methylamino]ethoxy]-1H-indol-2-yl]quinolin-2(1H)-one、hF4-3C5、ZK-CDK、IMC-EB10、LS-104、CYC-116、OSI-930、PF-337210、JNJ-26483327、SSR-106462、R-1530、PRS-050、TG-02、SC-71710、SB-1578、AMG-191、AMG-820、Sulfatinib、Lucitanib hydrochloride、JNJ-28312141、Ilorasertib、PLX-5622、ARRY-382、TAS-115、Tanibirumab、Henatinib、LY-2457546、PLX-7486、FPA-008、NVP-AEE-788、cgi-1842、RAF-265、MK-2461、SG-00529、Rebastinib、Golvatinib、Roniciclib、BVT-II、X-82、XV-615、KD-020、Lestaurtinib、Delphinidin、Semaxanib、Vatalanib、OSI-632、Telatinib、Alacizumab pegol、ATN-224、Tivozanib、XL-999、Icrucumab、Foretinib、Crenolanib besylate、R-406、Brivanib、Pegdinetanib、TG-100572、Olaratumab、Fostamatinib disodium、BMS-690514、AT-9283、MGCD-265、Quizartinib、ENMD-981693、Famitinib、Anlotinib、Tovetumab、PLX-3397、Fruquintinib、(-)-Epigallocatechin、Midostaurin、NSC-706456、Orantinib、Cediranib、Dovitinib、XL-647、Motesanib、Linifanib、Brivanib、Cediranib、Apatinib、Fedratinib、Pacritinib、Ramucirumab、Intedanib、Masitinib、Elemene、Dihydroartemisinin、WS-1442、Itranazole、Leflunomide、Dihydroartemisinin、Imatinib、Sorafenib、Sunitinib、Dasatinib、Pazopanib、Vandetanib、Axitinib、Regorafenib、Cabozantinib及びPonatinib等のチロシンキナーゼ阻害剤、ハイドロコルチゾン、トリアムシノロン、フルオシノロン、デキサメタゾン、ベタメタゾン等のステロイド、イソプロピルウノプロストン、ラタノプロスト、ビマトプロスト、トラボプロスト等のプロスタグランジン誘導体、シクロスポリン、シロリムス、FK506等の免疫抑制剤、アゼラスチン等の抗アレルギー剤、インドメタシン、ブロムフェナク、ジクロフェナク等の非ステロイド性抗炎症剤、パゾパニブ、SU5416、バラチニブ、ラニビズマブ、ベバシズマブなどの血管新生阻害薬、ニカルジピン、ニトレンジピン等の循環改善薬、ビタミンEなどの抗酸化剤、アセタゾラミド、ブリンゾラミドなどの炭酸脱水酵素阻害剤、チモロール、カルテオロール等のβ受容体遮断薬、ビタミンA誘導体等のビジュアルサイクルモジュレーター、毛様体栄養因子(CNTF)、脳由来神経栄養因子(BDNF)等の栄養因子や神経成長因子(NGF)、幹細胞増殖因子(HGF)等の成長因子、ペガプタニブのようなアプタマー、各種アンチセンス核酸、siRNAのような核酸医薬、ルセンティス、IgGなどの抗体・ペプチド製剤、特開2006−96739、特開2011−37844、特開2005−232149、特開2006−273851、特開2006−306861、特開2008−266294などに記載のVEGF阻害剤、特開2007−230993、特開2008−074829、特開2008−143889、特開2008−143890、特開2008−143891、特開2009−007344、特開2009−084274などに記載のグルココルチコイド受容体結合活性を有する化合物、RU24858などの選択的グルココルチコイド受容体アゴニスト、フルオロウラシルなどの抗癌剤、トファシチニブなどのヤヌスキナーゼ阻害剤、ルボキシスタウリンメシレートなどのプロテインキナーゼ阻害剤、等が挙げられる。
[式中、
R1は水素原子、ハロゲン原子、ヒドロキシル基、C1-6アルキル基、1個若しくは複数個のハロゲン原子で置換されたC1-6アルキル基、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、;
R2は水素原子、C1-6アルキル基、C1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す]
で表される化合物又はその塩を使用することが好適である。より好ましくは、R1が、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、R2がC1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す上記式(1)の化合物またはその塩であり、さらに好ましくは、R1が、1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、R2が1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す上記式(1)の化合物またはその塩である。
「C1-6アルキル基」とは、炭素原子数1〜6個の直鎖又は分枝のアルキル基を示し、炭素原子数が1〜4個の直鎖又は分枝のアルキル基が好ましい。具体例としてメチル基、エチル基、n−プロピル基、n−ブチル基、n−ペンチル基、n−ヘキシル基、イソプロピル基、イソブチル基、sec−ブチル基、tert−ブチル基、イソペンチル基などが挙げられる。
「1個若しくは複数個のヒドロキシル基で置換された」とは、前記C1-6アルキル基が、1個以上、置換可能な数以下の個数のヒドロキシル基で置換されていることを示す。ヒドロキシル基の個数は1又は2個の場合が好ましく、1個の場合が特に好ましい。
で表される2−[[[2−[(ヒドロキシアセチル)アミノ]−4−ピリジニル]メチル]チオ]−N−[4−(トリフルオロメトキシ)フェニル]−3−ピリジンカルボキサミド又はその塩である。米国特許出願公開第2007/0149574号明細書には、式(2)で表される化合物などが、VEGF誘発HUVEC増殖反応評価系を用いた試験系において細胞増殖阻害作用を示すこと、マウス担癌モデルを用いた試験系において腫瘍増殖抑制作用を示すこと、ラットアジュバント関節炎モデルを用いた試験系において足浮腫抑制作用を示すこと、ラット脈絡膜血管新生モデルを用いた試験系において脈絡膜血管新生阻害作用を示すことが記載されている。さらに、それらの薬理作用から式(2)で表される化合物は、医薬として有用であり、特に癌、関節リウマチ、加齢性黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫などの疾患の予防または治療剤として期待されることが記載されている。
また、米国特許出願公開第2012/0116088号明細書には、式(2)で表される化合物のベンゼンスルホン酸塩、その結晶、その結晶多形およびそれらの製造方法が記載されており、式(2)で表される化合物のベンゼンスルホン酸塩は、保存安定性に優れ、反復経口投与を行っても胃に鉱質沈着が認められないことが記載されている。
本発明における薬物に幾何異性体、互変異性又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。
さらに本発明における薬物に結晶多形が存在する場合は、結晶多形体も本発明の範囲に含まれる。
本発明における有機溶媒は、ポリエチレングリコール(PEG)、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される。
上記有機溶媒としてのポリエチレングリコール(PEG)は、エチレングリコールが重合したポリエーテルであり、化学式HO(CH2CH2O)nHで表され、nは重合数である。
上記有機溶媒としてのジメチルスルホキシド(DMSO)は、化学式CH3SOCH3で表される化合物である。
上記有機溶媒としてのN−メチルピロリドンは、テトラヒドロフランとポリエチレングリコールからなる下記式(4)で表される化合物である。
上記ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される有機溶媒のほか、さらに、水、エタノール、N,N−ジメチルアセトアミド等の医薬品の添加物として使用可能な溶媒を含有することができる。特に、ポリペプチドAを溶解する観点から、水を含有することが好ましい。
本発明における医薬組成物は、必要に応じて添加剤を用いることができ、添加剤としては、界面活性剤、緩衝化剤、等張化剤、安定化剤、防腐剤、抗酸化剤、高分子量重合体等を加えることができる。
ショ糖脂肪酸エステルとしては、ショ糖ステアリン酸エステル等が挙げられる。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(1)で表される化合物又はその塩、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、ポリエチレングリコール、及び、水のみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(2)で表される化合物又はその塩、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、ポリエチレングリコール、及び、水のみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、薬物、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(1)で表される化合物又はその塩、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(2)で表される化合物又はその塩、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
放出率(%)=[薬物の放出量(質量)]/[薬物の初期量(投与量)(質量)]×100
放出率としては、例えば1日経過後の放出率が、60%以下であることが好ましく、1〜50%であることがより好ましく、1〜45%であることがさらに好ましい。また、6日後の放出率が、97%以下であることが好ましく、5〜95%であることがより好ましく、10〜90%であることがさらに好ましい。
上記徐放性は、本発明の医薬組成物や後述する薬物用徐放性付与剤が体内に投与された場合、塊、いいかえると、いわゆる「デポ(depot)」を生じることにより、これら医薬組成物等に存在する薬物がデポからゆっくりと放出されることで達成される。
本発明の薬物用徐放性付与剤は、薬物に徐放性を付与することができるものであり、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドと、有機溶媒とを含有する。当該有機溶媒は、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である。各成分及び追加の添加剤等の詳細に関しては、上述した医薬組成物の記載をそのままこの徐放性付与剤に適用できる。例えば、ポリペプチド及び溶媒の詳細は、上述したとおりであり、上述した添加剤を加えることができる点も上記医薬組成物の説明と同様である。本発明の徐放性付与剤:薬物の割合が、例えば、質量比で、0.01:99.99〜30:70、好ましくは、0.1:99.9〜25:75、より好ましくは、0.5:99.5〜20:80、さらに好ましくは、1:99〜15:85、特に好ましくは、1:99〜12:88であることが適当である。
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は組成物100mL中の含量である。
薬物 4g
ポリペプチドA 0.1g
PEG400/水(体積比9/1) 適量
薬物 4g
ポリペプチドA 0.5g
PEG400/水(体積比9/1) 適量
薬物 4g
ポリペプチドA 0.1g
PEG400/水(体積比8/2) 適量
薬物 4g
ポリペプチドA 0.5g
PEG400/水(体積比8/2) 適量
薬物 4g
ポリペプチドA 0.1g
DMSO 適量
薬物 4g
ポリペプチドA 0.5g
DMSO 適量
各種溶液の薬物溶解能を検討した。
1−1.試験方法
上記式(2)で表される化合物(2−[[[2−[(ヒドロキシアセチル)アミノ]−4−ピリジニル]メチル]チオ]−N−[4−(トリフルオロメトキシ)フェニル]−3−ピリジンカルボキサミド、以下、薬物Aともいう;米国特許出願公開第2007/0149574号明細書記載の方法に準じて調製した)をDMSO(GAYLORD)、PEG400(ナカライテスク)又は水からなる各種溶媒(合計1mL)に加え、室温(25℃)で終夜(8時間)撹拌したときの性状を目視にて確認した。
各種ゲル化剤のデポ(塊)の形成を検討した。
2−1.試験方法
各種ゲル化剤を0.1%(w/v)となるようにDMSO/水(体積比9:1)の溶媒に配合し(100mLのDMSO/水に対してゲル化剤が0.1質量%含有)、組成物1〜6を調製した。ダルベッコリン酸緩衝液(−)(Sigma−Aldrich製、製品番号D−5652)に塩化カルシウム二水和物及び塩化マグネシウム六水和物を溶解させてダルベッコリン酸緩衝液(+)を調製した。各組成物0.005mLをダルベッコリン酸緩衝液(+)1mLに投与し、デポの形成を目視にて確認した。デポの形成は、塊ができていたらデポが形成されているものと評価した。
2−2.試験結果及び考察
試験結果を表2に示す。表2から分かるように、各種ゲル化剤のなかで、ポリペプチドAのみが体積比でDMSO/水(9:1)溶液でもデポを形成した。従って、本発明の徐放性付与剤は、薬物と共に体内に投与されるとデポを形成して、当該薬物を徐放し得ることが示された。
ポリペプチドAの溶媒を検討した。
3−1.試験方法
各種溶媒0.09mLに1%(w/v)ポリペプチドA水溶液(水100mLに対してポリペプチドAが1質量%含有)を0.01mL加えて撹拌し、組成物2〜6及び比較例6〜7を調製した。そのうち0.005mLをダルベッコリン酸緩衝液(+)1mLに投与し、デポの形成を目視にて確認した。
3−2.試験結果及び考察
試験結果を表3に示す。表3から分かるように、ポリペプチドAは、DMSO、PEG200、PEG400、グリコフロール(重合数が主に1〜4の混合物)及びN−メチルピロリドンを溶媒として用いた場合にデポを形成した。一方、エタノール及びN,N−ジメチルアセトアミドを溶媒用いた場合には、デポを形成しなかった。従って、本発明の徐放性付与剤は、薬物と共に体内に投与されるとデポを形成して、当該薬物を徐放し得ることが示された。
デポからの薬物徐放性を検討した。
4−1.被験組成物の調製
薬物A0.25gをPEG400(ナカライテスク)8mLに加え、撹拌溶解し、組成物Aを得た。
組成物A1.6mLに水0.4mLを加え、撹拌溶解し、組成物Bを得た。
1%(w/v)のポリペプチドA水溶液(水100mLに対してポリペプチドAが1質量%含有)1mLを規格瓶に1mL採取し、−35〜30℃にて凍結乾燥して、組成物A1.6mL及び水0.4mLを加え、撹拌混合し、組成物Cを得た。
組成物C0.7mLに組成物B0.7mLを加え、撹拌混合し、組成物Dを得た。
組成物C0.2mLに組成物B0.8mLを加え、撹拌混合し、組成物Eを得た。
薬物Aを25mgをPEG400(ナカライテスク)1mLに加え、撹拌溶解し、組成物Fを得た。
10gのステアリン酸ポリオキシル40(日光ケミカルズ)とダルベッコリン酸緩衝液(シグマアルドリッチ)9.6gに水を加え、全量を1Lとした(放出溶媒)。
37℃に加温した放出溶媒を20mLずつ規格瓶に投入し、組成物C〜F試験液を0.01mLずつ投入した後、37℃、86rpmで6日間撹拌した。放出溶媒中に放出された薬物Aの量を高速液体クロマトグラフィー(HPLC)を用いて定量し、放出率(%)を算出した。放出率は、以下の式に基づいて算出した。
放出率(%)=[薬物の放出量(質量)]/[薬物の初期量(投与量)(質量)]×100
上記式において、例えば、各組成物の試験液を放出溶媒に投入した日を0日とし、1日(24時間)経過後を1日後として放出率を算出する場合、[薬物の初期量(投与量)(質量)]は、薬物投入時(0日)の薬物の投入量であり、「薬物の放出量(質量)」は、1日経過後の薬物の放出量である。
試験結果を表4に示す。表4から分かるように、組成物C〜Eは、放出溶媒に投入後、デポを形成し、1日〜6日間かけて薬物Aを徐放した。
Claims (17)
- 薬物と、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドと、有機溶媒とを含有する医薬組成物であって、
前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、医薬組成物。 - さらに、水を含有する、請求項1記載の医薬組成物。
- 前記有機溶媒と水の体積比が99:1〜60:40である、請求項2記載の医薬組成物。
- 前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールの平均分子量が90から2200の範囲内である、請求項1〜3のいずれか一項に記載の医薬組成物。
- 前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールがPEG400である、請求項1〜3のいずれか一項に記載の医薬組成物。
- 前記薬物の含有量が、0.01〜30%(w/v)である、請求項1〜5のいずれか一項に記載の医薬組成物。
- 前記Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドの含有量が、0.001〜5%(w/v)である、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記有機溶媒の含有量が70〜99.99%(w/w)である、請求項1〜7のいずれか一項に記載の医薬組成物。
- 薬物、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、ポリエチレングリコール、及び水のみから実質的になる、請求項1〜8のいずれか一項に記載の医薬組成物。
- 薬物、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド、及びジメチルスルホキシドのみから実質的になる、請求項1に記載の医薬組成物。
- 薬物が、2−[[[2−[(ヒドロキシアセチル)アミノ]−4−ピリジニル]メチル]チオ]−N−[4−(トリフルオロメトキシ)フェニル]−3−ピリジンカルボキサミド又はその塩である、請求項1〜10のいずれか一項に記載の医薬組成物。
- 眼疾患を予防又は治療するための、請求項1〜12のいずれか一項に記載の医薬組成物。
- 硝子体内又は前房内投与用である、請求項13に記載の医薬組成物。
- 薬物徐放用である、請求項13又は14に記載の医薬組成物。
- Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチドと、有機溶媒とを含有する薬物用徐放性付与剤であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、徐放性付与剤。
- 薬物に、Ac−(Arg−Ala−Asp−Ala)4−NH2で表されるポリペプチド及び有機溶媒を添加する工程を含む、薬物に徐放性を付与する方法であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN−メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、方法。
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