JP2013538224A - エキセンジンリンカー複合体を含むプロドラッグ - Google Patents
エキセンジンリンカー複合体を含むプロドラッグ Download PDFInfo
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- JP2013538224A JP2013538224A JP2013528685A JP2013528685A JP2013538224A JP 2013538224 A JP2013538224 A JP 2013538224A JP 2013528685 A JP2013528685 A JP 2013528685A JP 2013528685 A JP2013528685 A JP 2013528685A JP 2013538224 A JP2013538224 A JP 2013538224A
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- Prior art keywords
- exendin
- hydrogel
- linker
- prodrug
- moiety
- Prior art date
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- Granted
Links
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Abstract
Description
から放出後の天然ペプチド本来の薬理の回復とを兼ね備えている。
Dは、エキセンジン部分を表し;そして
−Lは、式(I)
R1は、C1-4アルキル、好ましくはCH3から選ばれ;
R2、R2aは、H及びC1-4アルキルからなる群より独立して選ばれる)
によって表される生物活性のないリンカー部分−L1
(ここにおいて、L1は、1つのL2−Zで置換され、そして場合によりさらに置換されるが、但し、式(I)中のアスタリスクでマークされた水素は、置換基によって置き換えられず、そしてここにおいて、
L2は、単化学結合又はスペーサーであり;そして
Zは、ヒドロゲルである)
である]
の共有結合性エキセンジンプロドラッグを含むプロドラッグ又はその薬学的に許容しうる
塩によって達成される。
(i)配列中の1つ又はそれ以上のアミノ酸残基が、N末端修飾を含む異なるアミノ酸残基によって置き換えられた、エキセンジン−4類似体及びアミド化エキセンジン−4類似体;
(ii)エキセンジン−4の切断及び延長形態並びにアミド化された切断及び延長形態;
(iii)配列中の1つ又はそれ以上のアミノ酸残基が異なるアミノ酸残基によって置き換えられた、切断及び延長エキセンジン−4並びにアミド化された切断及び延長形態;
(iv)GLP−1及びアミド化されたGLP−1;
(v)N末端修飾を含む、配列中の1つ又はそれ以上のアミノ酸残基が異なるアミノ酸残基によって置き換えられた、GLP−1−類似体及びアミド化されたGLP−1類似体;
(vi)切断及び延長GLP−1並びにアミド化された切断及び延長形態;
(vii)配列中の1つ又はそれ以上のアミノ酸残基が異なるアミノ酸残基によって置き換えられた、切断GLP−1及びアミド化された切断形態;
(viii)すでに知られた物質AVE−0010/ZP−10/リキシセナチド(Sanofi-Aventis Zealand Pharma;配列ID21)、BAY−73−7977(Bayer)、TH−0318、BIM−51077(Ipsen, Tejin, Roche)、NN2211(Novo Nordisk)、LY315902;
を含むが、それらに限定されるわけではないエキセンジン−3又はエキセンジン−4アゴニストである。
H−desPro36−エキセンジン−4−Lys6−NH2、
H−des(Pro36,37)−エキセンジン−4−Lys4−NH2及び
H−des(Pro36,37)−エキセンジン−4−Lys5−NH2
を含む群から選ばれるもの
又はその薬理学的に許容しうる塩
であってもよい。
desPro36[Asp28]エキセンジン−4(1−39)、
desPro36[IsoAsp28]エキセンジン−4(1−39)、
desPro36[Met(O)14,Asp28]エキセンジン−4(1−39)、
desPro36[Met(O)14,IsoAsp28]エキセンジン−4(1−39)、
desPro36[Trp(O2)25,Asp28]エキセンジン−2(1−39)、
desPro36[Trp(O2)25,IsoAsp28]エキセンジン−2(1−39)、
desPro36[Met(O)14Trp(O2)25,Asp28]エキセンジン−4(1−39)及び
desPro36[Met(O)14Trp(O2)25,IsoAsp28]エキセンジン−4(1−39)
を含む群から選ばれるもの
又はその薬理学的に許容しうる塩
であってもよい。
H−(Lys)6−des Pro36[Asp28]エキセンジン−4(1−39)−Lys6−NH2
des Asp28Pro36,Pro37,Pro38エキセンジン−4(1−39)−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Asp28]エキセンジン−4(1−39)−NH2、
H−Asn−(Glu)5 des Pro36,Pro37,Pro38[Asp28]エキセンジン−4(1−39)−NH2、
des Pro36,Pro37,Pro38[Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36[Trp(O2)25,Asp28]エキセンジン−4
(1−39)−Lys6−NH2、
H−des Asp28 Pro36,Pro37,Pro38[Trp(O2)25]エキセンジン−4(1−39)−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]エキセンジン−4(1−39)−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]エキセンジン−4(1−39)−NH2、
des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36[Met(O)14,Asp28]エキセンジン−4(1−39)−Lys6−NH2、
des Met(O)14 Asp28Pro36,Pro37,Pro38エキセンジン−4(1−39)−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−NH2、
des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−Lys6−NH2、
H−Asn−(Glu)5 des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36[Met(O)14 Trp(O2)25,Asp28]エキセンジン−4(1−39)−Lys6−NH2、
des Asp28 Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25]エキセンジン−4(1−39)−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]エキセンジン−4(1−39)−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Met(O)14,Asp28]エキセンジン−4(1−39)−NH2、
des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−(Lys)6−des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2、
H−Asn−(Glu)5−des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]エキセンジン−4(1−39)−(Lys)6−NH2
を含む群から選ばれるもの
又はその薬理学的に許容しうる塩
であってもよい。
[配列ID番号:1]エキセンジン−4
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPPS−NH2
[配列ID番号:2]エキセンジン−3
HSDGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPPS−NH2
[配列ID番号:3]
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG P
[配列ID番号:4]
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG Y
[配列ID番号:5]
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG
[配列ID番号:6]
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG−NH2
[配列ID番号:7]
HGEGTFTSDL SKQMEEEAVR LFIEWLKN−NH2
[配列ID番号:8]
HGEGTFTSDL SKQLEEEAVR LFIEFLKNGG PSSGAPPPS−NH2
[配列ID番号:9]
HGEGTFTSDL SKQLEEEAVR LFIEFLKN−NH2
[配列ID番号:10]
HGEGTFTSDL SKQLEEEAVR LAIEFLKN−NH2
[配列ID番号:ll]
HGEGTFTSDL SKQLEEEAVR LFIEWLKNGG PSSGAPPPS−NH2
[配列ID番号:12]HGDGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPPS−NH2
[配列ID番号13]GLP−l(7−36)アミドHAEGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
[配列ID番号14]
HSEGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
[配列ID番号15]GLP−l(7−37)
HAEGTFTSDV SSYLEGQAAK EFIAWLVKGRG
[配列ID番号16]
HAXaaGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
Xaa=P、F、Y
[配列ID番号17]
HXaaEGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
Xaa=T、a−アミノ酪酸、D−Ala、V、Gly、
[配列ID番号18]
HaEGTFTSDV SSYLEGQAAK EFIAWLVKGG
[配列ID番号19]
R−HAEGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
R=アセチル、ピログルタミル、N−2−ヒドロキシベンゾイル、N−トランス−3−ヘキサノイル
[配列ID番号20]
HXaaAEGTFTSDV SSYLEGQAAK EFIAWLVKGR−NH2
Xaa=6−アミノ−ヘキサノイル。
[配列ID番号21]
AVE−0010/ZP−10/リキシセナチドHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK−NH2
[配列ID番号22]
Arg34,Lys26(Nε(γ−グルタミル(Nα−ヘキサデカノイル)))GLP−1(7−37)[リラグルチド]HAEGTFTSDV SSYLEGQAAXaaEFIAWLVRGRG
Xaa=Lys(Nε(γ−グルタミル(Nα−ヘキサデカノイル)))
好ましくは、エキセンジンは、配列ID1、ID13、ID15、ID21又はID22を有する。
ー試薬及び骨格鎖試薬の部分である化学官能基のことである。
用語は、オリゴ−又はポリマー分子鎖のことである。
Dは、エキセンジン部分を表し;そして
−Lは、式(I)
R1は、C1-4アルキル、好ましくはCH3から選ばれ;
R2、R2aは、H及びC1-4アルキルからなる群より独立して選ばれる)
によって表される生物活性のないリンカー部分−L1
(ここにおいて、L1は、1つのL2−Zで置換され、そして場合によりさらに置換されるが、但し、式(I)中のアスタリスクでマークされた水素は、置換基によって置換されず、そしてここにおいて、
L2は、単化学結合又はスペーサーであり;そして
Zは、ヒドロゲルである)
である]
の共有結合性エキセンジンプロドラッグを含むプロドラッグ又はその薬学的に許容しうる塩に関する。
[式中、Lは、式(Ia)又は(Ib):
R9、R9a、R9bは、H;T;及びC1-50アルキル;C2-50アルケニル;又はC2-50アルキニルからなる群より独立して選ばれ、ここにおいてT;C1-50アルキル;C2-50アルケニル;及びC2-50アルキニルは、同一又は異なる1つ又はそれ以上のR10で場合により置換されており、そしてC1-50アルキル;C2-50アルケニル;及びC2-50アルキニルは、T、−C(O)O−;−O−;−C(O)−;−C(O)N(R11)−;−S(O)2N(R11)−;−S(O)N(R11)−;−S(O)2−;−S(O)−;−N(R11)S(O)2N(R11a)−;−S−;−N(R11)−;−OC(O)R11−;−N(R11)C(O)−;−N(R11)S(O)2−;−N(R11)S(O)−;−N(R11)C(O)O−;−N(R11)C(O)N(R11a)−;及び−OC(O)N(R11R11a)−からなる群より選ばれる1つ又はそれ以上の基によって場合により中断されており;
Tは、フェニル;ナフチル;インデニル;インダニル;テトラリニル;C3-10シクロアルキル;4〜7員ヘテロシクリル;又は9〜11員ヘテロビシクリルからなる群より選ばれ、ここにおいて、Tは、同一又は異なる1つ又はそれ以上のR10で場合により置換されており;
R10は、ハロゲン;CN;オキソ(=O);COOR12;OR12;C(O)R12;C(O)N(R12R12a);S(O)2N(R12R12a);S(O)N(R12R12a);S(O)2R12;S(O)R12;N(R12)S(O)2N(R12aR12b);SR12;N(R12R12a);NO2;OC(O)R12;N(R12)C(O)R12a;N(R12)S(O)2R12a;N(R12)S(O)R12a;N(R12)C(O)OR12a;N(R12)C(O)N(R12aR12b);OC(O)N(R12R12a);又はC1-6アルキルであり、ここにおいて、C1-6アルキルは、同一又は異なる1つ又はそれ以上のハロゲンで場合により置換されており;
R11、R11a、R12、R12a、R12bは、H;又はC1-6アルキルからなる群より独立して選ばれ、ここにおいて、C1-6アルキルは、同一又は異なる1つ又はそれ以上のハロゲンで場合により置換されている。
R9、R9a、R9bは、H;Z;T;及びC1-50アルキル;C2-50アルケニル;又はC2-50アルキニルからなる群より独立して選ばれ、ここにおいてT;C1-50アルキル;C2-50アルケニル;及びC2-50アルキニルは、同一又は異なる1つ又はそれ以上のR10で場合に
より置換されており、そしてC1-50アルキル;C2-50アルケニル;及びC2-50アルキニルは、T、−C(O)O−;−O−;−C(O)−;−C(O)N(R11)−;−S(O)2N(R11)−;−S(O)N(R11)−;−S(O)2−;−S(O)−;−N(R11)S(O)2N(R11a)−;−S−;−N(R11)−;−OC(O)R11−;−N(R11)C(O)−;−N(R11)S(O)2−;−N(R11)S(O)−;−N(R11)C(O)O−;−N(R11)C(O)N(R11a)−;及び−OC(O)N(R11R11a)からなる群より選ばれる1つ又はそれ以上の基によって場合により中断されており;
Tは、フェニル;ナフチル;インデニル;インダニル;テトラリニル;C3-10シクロアルキル;4〜7員ヘテロシクリル;又は9〜11員ヘテロビシクリルからなる群より選ばれ、ここにおいてtは、同一又は異なる1つ又はそれ以上のR10で場合により置換されており;
R10は、Z;ハロゲン;CN;オキソ(=O);COOR12;OR12;C(O)R12;C(O)N(R12R12a);S(O)2N(R12R12a);S(O)N(R12R12a);S(O)2R12;S(O)R12;N(R12)S(O)2N(R12aR12b);SR12;N(R12R12a);NO2;OC(O)R12;N(R12)C(O)R12a;N(R12)S(O)2R12a;N(R12)S(O)R12a;N(R12)C(O)OR12a;N(R12)C(O)N(R12aR12b);OC(O)N(R12R12a);又はC1-6アルキルであり、ここにおいてC1-6アルキルは、同一又は異なる1つ又はそれ以上のハロゲンで場合により置換されており;
R11、R11a、R12、R12a、R12bは、H;Z;又はC1-6アルキルからなる群より独立して選ばれ、ここにおいてC1-6アルキルは、同一又は異なる1つ又はそれ以上のハロゲンで場合により置換されており;
但し、R9、R9a、R9b、R10、R11、R11a、R12、R12a、R12bの1つだけがZである。
mは2から4の整数である)
の少なくとも1つのスペーサーに結合している。
によって表される構造を有する。
mは2から4の整数である)
の少なくとも1つのスペーサーに結合している。
他の点線はHypへの結合を示し、そして
pは、0から10の整数である)
の少なくとも1つのスペーサーに結合している。
骨格鎖試薬合成の好ましい出発物質は、4−アームPEGテトラアミン又は8−アームPEGオクタアミンであり、PEG試薬は、2000〜10000ダルトン、最も好ましくは2000〜5000Daの範囲の分子量を有する。このようなマルチアームPEG−誘導体に、リシン残基を逐次的にカップリングして超分枝骨格鎖試薬を形成する。リシンは、カップリング工程中に保護基によって部分的に又は完全に保護することができ、そしてまた、最終的な骨格鎖試薬は、保護基を含んでもよいことが理解される。好ましい構成ブロックは、ビス−bocリシンである。別法として、リシン残基の逐次付加の代わりに、樹枝状ポリリシン部分を最初に構成し、その後、4−アームPEGテトラアミン又は8−アームPEGオクタアミンにカップリングさせてもよい。32個のアミノ基を担持する骨格鎖試薬を得ることが望ましく、結果的に、7個のリシンを4−アームPEGの各アームに結合させるか、又は5個のリシンを8−アームPEGの各アームに結合させる。別の実施態様において、マルチアームPEG誘導体は、テトラ−又はオクタカルボキシPEGである。この場合、樹枝状部分は、グルタル又はアスパラギン酸から生成してもよく、そして生成した骨格鎖試薬は、32個のカルボキシ基を担持する。骨格鎖試薬の官能基のすべて又は一部は、塩として、遊離形態で存在するか、又は保護基に結合してもよいことが理解される。実際的な理由のため、PEG−アーム当たりリシンの骨格鎖試薬の数は、6〜7個、より好ましくは約7個であることが理解される。
(a)マレイミド官能化ヒドロゲル微粒子を含む水性懸濁液を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で、L2*の化学官能基がチオール基を含む本発明のエキセンジン−リンカー試薬を含む溶液と接触させてエキセンジン−リンカー−ヒドロゲル複合体を生成させる工程;
(b)場合により、工程(a)からのエキセンジン−リンカー−ヒドロゲル複合体をpH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で34Da〜500Daのチオール含有化合物により処理する工程;
を含む方法である。
(a)チオール官能化ヒドロゲル微粒子を含む水性懸濁液を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で、L2*の化学官能基がマレイミド基を含む本発明のエキセンジン−リンカー試薬を含む溶液と接触させてエキセンジン−リンカー−ヒドロゲル複合体を生成させる工程;
(b)場合により、工程(a)からのエキセンジン−リンカー−ヒドロゲル複合体をpH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で100〜300Daのマレイミド含有化合物により処理する工程;
を含む方法である。
(a)式C(A'−X1)4(式中、A'−X1はHyp又はHypの前駆体に結合する前のAを表し、そしてX1は適切な官能基である)の化合物を、式Hyp'−X2(式中、Hyp'−X2はAに結合する前のHyp又はHypの前駆体を表し、そしてX2はX1と反応する適切な官能基である)の化合物と反応させる工程;
(b)場合により工程(a)から生成した化合物を1つ又はそれ以上のさらなる工程で反応させて少なくとも4つの官能基を有する式C(A−Hyp)4の化合物を得る工程;
(c)工程(b)から生成した化合物の少なくとも4つの官能基をポリ(エチレングリオール)ベースのクロスリンカー前駆体と反応させ、ここにおいて、C(A−Hyp)4の反応性官能基の総数と比較してクロスリンカー前駆体の活性なエステル基を化学量論量未満の量で用いてヒドロゲルを得る工程;
(d)工程(c)のヒドロゲル骨格鎖中に残っている未反応の官能基(ヒドロゲル中に含まれる骨格鎖の反応性官能基を表す)を生物活性部分及び一過性プロドラッグリンカーの共有結合性複合体と反応させるか又は最初に未反応の官能基を一過性プロドラッグリンカー、続いて生物活性部分と反応させる工程;
(e)場合により残っている未反応の官能基にキャップ形成して本発明のプロドラッグを得る工程;
を含む。
バルク重合では、骨格鎖試薬及びクロスリンカー試薬をアミン/活性エステル2:1〜1.05:1の比率で混合する。
より好ましくは、塩基は、分散相及びDMSOの両方において非プロトン性、非求核性、十分に可溶性、アミン塩基、そして非毒性である。最も好ましくは、塩基は、N,N,N',N'−テトラメチルエチレンジアミン(TMEDA)である。塩基存在下での撹拌を、1〜16時間継続する。
である。
{式中、
Dは、エキセンジン部分を表し;そして
L*は、式(IV)、
R1は、C1-4アルキル、好ましくはCH3から選ばれ;
R2、R2aは、H及びC1-4アルキルからなる群より独立して選ばれる)
によって表される生物活性のないリンカー試薬であり、
L*は、1つのL2*で置換されており、そして場合によりさらに置換されるが、但し、式(IV)中のアスタリスクでマークされた水素は、置換基によって置き換えられることはなく、そしてここにおいて、
L2*は、L*に結合されたスペーサーであり、そしてヒドロゲルに結合するための化学官能基を含む}
である。
(a)微粒子形態で本発明のエキセンジンヒドロゲルプロドラッグを製造する工程;
(b)微粒子を篩にかける工程;
(c)25〜80μmのプロドラッグビーズ直径の画分を選ぶ工程;
(d)工程(c)のビーズ画分を注射に適した水性緩衝溶液中で懸濁する工程;
を含む、注射針で注射可能なプロドラッグの製造方法である。
(i)緩衝剤:所望の範囲にpHを維持する生理学的に許容しうるバッファー、例えばナトリウムのリン酸塩、炭酸水素塩、コハク酸塩、ヒスチジン、クエン酸塩及び酢酸塩、硫酸塩、硝酸塩、塩化物、ピルビン酸。また、酸中和剤、例えばMg(OH)2又はZnCO3を用いてもよい。緩衝能力は、pH安定性に最も感受性の状態に合わせて調整してもよい。
(ii)等張性調整剤:注射デポ剤での浸透圧の違いによる細胞損傷から生じることがある疼痛を最小限にするため。例として、グリセリン及び塩化ナトリウムがある。有効濃度は、血清について285〜315mOsmol/kgの推定浸透圧を用いて浸透圧測定によって決定することができる。
(iii)防腐剤及び/又は抗菌剤:反復投与の非経口製剤では、患者が注射時に感染するリスクを最小限にするために十分な濃度で防腐剤を添加する必要があり、そして対応する規制上の要件は確立されている。典型的な防腐剤としては、m−メタクレゾール、フェノール、メチルパラベン、エチルパラベン、プロピルパラベン、ブチルパラベン、クロロブタノール、ベンジルアルコール、硝酸フェニル水銀、チメロソール(thimerosol)、ソルビン酸、ソルビン酸カリウム、安息香酸、クロロクレゾール、及び塩化ベンザルコニウムが含まれる。
(iv)安定剤:安定化は、タンパク質安定化力を強化することによって、変性したステーター(stater)の不安定化によって、又は賦形剤をタンパク質に直接結合することによって達成される。安定剤は、アミノ酸、例えばアラニン、アルギニン、アスパラギン酸、グリシン、ヒスチジン、リシン、プロリン、糖、例えばグルコース、スクロース、トレハロース、ポリオール、例えばグリセロール、マンニトール、ソルビトール、塩、例えばリン酸カリウム、硫酸ナトリウム、キレート剤、例えばEDTA、ヘキサホスフェート、リガンド、例えば二価金属イオン(亜鉛、カルシウム、など)、他の塩又は有機分子、例えばフェノール系誘導体であってもよい。さらに、オリゴマー又はポリマー、例えばシクロデキストリン、デキストラン、デンドリマー、PEG又はPVP又はプロタミン又はHSAを用いてもよい。
(v)抗吸着剤:主にイオン性若しくは非イオン性界面活性剤又は他のタンパク質又は可溶性のポリマーを用いて組成物又は組成物の容器の内表面にコーティングする又は競合的に吸着させる。例えば、ポロキサマー(プルロニック(Pluronic)F−68)、PEGドデシルエーテル(ブリッジ(Brij)35)、ポリソルベート20及び80、デキストラン、ポリエチレングリコール、PEG−ポリヒスチジン、BSA及びHSA並びにゼラチン。賦形剤の濃度及びタイプの選択は、回避すべき効果により左右されるが、典型的にCMC値のすぐ上では界面に界面活性剤の単層が形成される。
(vii)酸化防止」剤:抗酸化剤、例えばアスコルビン酸、エクトイン、メチオニン、グルタチオン、モノチオグリセロール、モリン、ポリエチレンイミン(PEI)、没食子酸プロピル、ビタミンE、キレート剤、例えばクエン酸、EDTA、ヘキサホスフェート、チオグリコール酸
(viii)増粘剤(viscosifiers)又は粘度増強剤(viscosity enhancers):バイアル及び注射器中で粒子の沈降を遅らせ、そして粒子の混合及び再懸濁を促進するため、そして懸濁液を注射し易くする(すなわち、注射器のプランジャーにおける力を弱める)ために用いられる。適切な増粘剤又は粘度増強剤は、例えば、カルボポール(Carbopol)940、カルボポールウルトレッツ(Carbopol Ultrez)10のようなカルボマー増粘剤、ヒドロキシプロピルメチルセルロース(ヒプロメロース、HPMC)又はジエチルアミノエチルセルロース(DEAE又はDEAE−C)のようなセルロース誘導体、コロイド状ケイ酸マグネシウム(Veegum)又はケイ酸ナトリウム、ヒドロキシアパタイトゲル、リン酸三カルシウムゲル、キサンタン、サチアガム(Satia gum)UTC30のようなカラゲナン、脂肪族ポリ(ヒドロキシ酸)、例えばポリ(D,L−又はL−乳酸)(PLA)及びポリグリコール酸(PGA)並びにそれらのコポリマー(PLGA)、D,L−ラクチド、グリコリド及びカプロラクトンのターポリマー、ポロキサマー、ポリ(オキシエチレン)−ポリ(オキシプロピレン)−ポリ(オキシエチレン)のトリブロック(例えばプルロニックR)を構成するための親水性ポリ(オキシエチレン)ブロック及び疎水性ポリ(オキシプロピレン)ブロック、ポリエチルエステルコポリマー、例えばポリエチレングリコールテレフタレート/ポリブチレンテレフタレートコポリマー、ショ糖酢酸イソ酪酸エステル(SAIB)、デキストラン又はその誘導体、デキストラン及びPEGの組み合わせ、ポリジメチルシロキサン、コラーゲン、キトサン、ポリビニルアルコール(PVA)及び誘導体、ポリアルキルイミド、ポリ(アクリルアミド−コ−ジアリルジメチルアンモニウム(DADMA))、ポリビニルピロリドン(PVP)、グリコサミノグリカン(GAG)、例えばデルマタン硫酸、コンドロイチン硫酸、ケラタン硫酸、ヘパリン、ヘパラン硫酸、ヒアルロナン、疎水性Aブロック、例えばポリ乳酸(PLA)又はポリ(ラクチド−コ−グリコリド)(PLGA)、及び親水性Bブロック、例えばポリエチレングリコール(PEG)又はポリビニルピロリドンで構成されたABAトリブロック又はABブロックコポリマーである。上記のポロキサマーと同様にこのようなブロックコポリマーは、逆熱ゲル化(reverse thermal gelation)挙動(投与を容易にするため室温で流体状態、そして注射後に体温でゾル−ゲル転移温度より上のゲル状態)を示すことがある。
(ix)拡散(spreading)又は拡散剤(diffusing agent):限定されるわけではないが、結合組織の細胞間隙に見出される多糖類、ヒアルロン酸のような組織間隙(intrastitial space)中の細胞外マトリックス成分の加水分解を通して結合組織の透過性を改良する。ヒアルロニダーゼのような拡散剤は、一時的に、細胞外マトリックスの粘度を低下さ
せ、そして注射された薬物の拡散を促進する。
(x)他の補助剤:例えば湿潤剤、粘度調整剤、抗生物質、ヒアルロニダーゼ。酸及び塩基、例えば塩酸及び水酸化ナトリウムは、製造中のpH調整に必要な補助剤である。
・本発明の組成物を再構成溶液と接触させる工程
を含む前記方法である。
(i)エキセンジン−ヒドロゲルプロドラッグを1つ又はそれ以上の賦形剤と混合し、
(ii)単回又は反復投与に相当する量を適切な容器に移し、
(iii)前記容器中の組成物を乾燥し、そして
(iv)容器を密閉すること
によって製造される。
(i)スルホニル尿素、例えば、クロルプロパミド、トラザミド、トルブタミド、グリブリド、グリピジド、グリメピリド、及び同様のものなど;
(ii)メグリチニド、例えば、レパグリニド、ナテグリニド又はミチグリニドなど;
(iii)グルカゴン様ペプチド−1(GLP−1)及びその模倣剤、グルコース−インスリン分泌性ペプチド(GIP)及びその模倣剤、エキセンジン及びその模倣剤、及びジペプチルプロテアーゼ阻害剤(Dipeptyl Protease Inhibitors)(DPPIV);
(iv)ビグアニド、例えば、メトホルミンなど;
(v)チアゾリジンジオン、例えば、ロシグリタゾン、ピオグリタゾン、トログリタゾン、イサグリタゾン(isaglitazone)(MCC−555として知られる)、2−[2−[(2R)−4−ヘキシル−3,4−ジヒドロ−3−オキソ−2H−1,4−ベンゾオキサジン−2−イル]エトキシ]−ベンゼン酢酸、シグリタゾン、ロシグリタゾン、特に5−[[4−[3,4−ジヒドロ−3−メチル−4−オキソ−2−キナゾリニルメトキシ]フェニル]メチル]−2,4−チアゾリジンジオン及び同様のものなど;
(vi)GW2570、及び同様のもの、
(vii)レチノイド−X受容体(RXR)モジュレーター、例えば、ターグレチン、9−シス−レチノイン酸、及び同様のものなど、
(viii)他のインスリン抵抗性改善剤(insulin sensitizing agents)、例えば、INS−1、PTP−1B阻害剤、GSK3阻害剤、グリコーゲンホスホリラーゼa阻害剤、フルクトース−1,6−ビスホスファターゼ阻害剤、及び同様のものなど;
(ix)レギュラーすなわち速効型、中間型、及び持効型インスリンを含むインスリン、吸入用インスリン並びにインスリン類似体、例えば天然アミノ酸配列において少しの違いを有するインスリン分子;
(x)L−783281、TE−17411、及び同様のものを含むが、それらに限定されるわけではないインスリンの小分子模倣剤;
(xi)ナトリウム依存性グルコース輸送体1及び/又は2阻害剤(SGLT1、SGLT2)、例えばKGA−2727、T−1095、T−1095A、SGL−0010、AVE 2268、SAR 7226、SGL−5083、SGL−5085、SGL−5094、ISI−388626、セルグリフロジン、ダパグリフロジン又はレモグリフロジンエタボナート、カナグリフロジン、フロリジン、及び同様のもの;
(xii)プラムリンチド、及び同様のものを含むが、それらに限定されないアミリン作動剤;
(xiii)グルカゴン拮抗剤、例えばAY−279955、及び同様のもの。
(xiv)腸ホルモン及び腸ホルモン活性のモジュレーター、例えばソマトスタチン、オキシントモジュリン、コレシストキニン、インクレチン、グレリン、PYY3−36、及び同様のもの。
Fmoc戦略によって合成された樹脂上のエキセンジン−4[配列ID番号(Seq ID No):1](約0.1mmol/g装填)をCASLO Laboratory Aps, Lyngby,デンマークから入手した。Fmoc戦略によって合成された樹脂上のリキシセナチド[配列ID番号21]及びGLP−1[配列ID番号13](約0.1mmol/g装填)をPeptide Specialty Laboratories, Heidelberg,ドイツから入手した。ペプチドは、完全に側鎖が保護されており、そして遊離N末端を有した。
Fmoc保護基除去のため、樹脂を、ピペリジン/DBU/DMF2/2/96(v/v/v)(2回、それぞれ10分)と共に撹拌し、そしてDMF(10回)で洗浄した。
RP−HPLCは、特に明記しない限り、Waters 600 HPLCシステム及びWaters 2487吸光度検出器に接続された100×20mm又は100×40mmC18 ReproSil-Pur 300 ODS-3 5μカラム(Dr. Maisch, Ammerbuch, Germany)において実施した。溶液A(H2O中の0.1%TFA)及び溶液B(アセトニトリル中の0.1%TFA)の線形勾配を用いた。生成物を含むHPLC画分を貯めて凍結乾燥した。
フラッシュクロマトグラフィ精製は、Biotage KP-Silシリカカートリッジ並びに溶離液としてn−ヘプタン及び酢酸エチルを用いてBiotage AB, スウェーデンからのIsolera Oneシステムにおいて実施した。生成物は、254nmで検出された。
ペプチド含量は、ヒドロゲル総質量(マレイミド官能化ヒドロゲル及びペプチドリンカーチオールの質量の合計)に対する%ペプチド質量として表した。ヒドロゲル中のペプチドリンカーチオールの質量(及び、従ってペプチド単独の質量)は、マレイミド官能化ヒドロゲルとの結合反応中のペプチドリンカーチオールの消費によって決定した。ペプチドリンカーチオールの消費は、エルマン試験(Ellman, G. L. et al., Biochem. Pharmacol., 1961, 7, 88-95)によって決定した。
収量3.85g(59%)無色のガラス状生成物1b
MS:m/z 1294.4=[M+5H]5+([M+5H]5+のMW計算値=1294.6)
MS:m/z 1151.9=[M+5H]5+([M+5H]5+のMW計算値=1152.0)
収量:4.01g(89%)無色のガラス状生成物1d、これをさらに精製することなく次の工程に用いた。
MS:m/z 1405.4=[M+6H]6+([M+6H]6+のMW計算値=1405.4)
MS:m/z 969.6=[M+7H]7+([M+7H]7+のMW計算値=969.7)
収量4.72g(82%)無色のガラス状生成物1f、これをさらに精製することなく次の工程に用いた。
MS:m/z 1505.3=[M+8H]8+([M+8H]8+のMW計算値=1505.4)
収量3.91g(100%)、ガラス状生成物骨格鎖試薬1g
MS:m/z 977.2=[M+9H]9+([M+9H]9+のMW計算値=977.4)
化合物1bを合成するため、iPrOH(無水)250mL中の4−アーム−PEG5000テトラアミン(1a)(50.0g,10.0mmol)の懸濁液にboc−Lys(boc)−OSu(26.6g,60.0mmol)及びDIEA(20.9mL,120mmol)を45℃で加え、そして混合物を30分間撹拌した。
収量:65.6g(74%)塊の多い白色固形物として1b
MS:m/z 937.4=[M+7H]7+([M+7H]7+のMW計算値=937.6)
収量:38.9g(86%)白色粉末として1c
MS:m/z 960.1=[M+6H]6+([M+6H]6+のMW計算値=960.2)
収量:21.0g(80%)白色固形物として1d
MS:m/z 1405.4=[M+6H]6+([M+6H]6+のMW計算値=1405.4)
収量:13.2g(96%)白色粉末として1e
MS:m/z 679.1=[M+10H]10+([M+10H]10+のMW計算値=679.1)
収量:12.8g、MW(90%)淡黄色の塊の多い固形物として1f
MS:m/z 1505.3=[M+8H]8+([M+8H]8+のMW計算値=1505.4)
収量:11.5g(89%)淡黄色フレークとして
MS:m/z 1104.9=[M+8H]8+([M+8H]8+のMW計算値=1104.9)
クロスリンカー試薬2dの合成
クロスリンカー試薬2dは、アジピン酸モノベンジルエステル(English, Arthur R. et al., Journal of Medicinal Chemistry, 1990, 33(1), 344-347)及びPEG2000から以下のスキームに従って製造した:
MS:m/z 813.1=[M+3H]3+([M+3H]3+のMW計算値=813.3)
収量:12.3g(定量的)黄色がかった油として2c。生成物をさらに精製することなく次の工程に用いた。
MS:m/z 753.1=[M+3H]3+(計算値=753.2)
収量: 8.73g(85%)無色の固形物としてクロスリンカー試薬2d
MS:m/z 817.8=[M+3H]3+(計算値=817.9g/mol)
遊離アミノ基を含むヒドロゲルビーズ(3)の製造
DMSO28.6mL中の1g 1200mg及び2d 3840mgの溶液をヘプタン100mL中の Arlacel P135(Croda International Plc)425mgの溶液に加えた。バッフルを備えた250ml反応器中、25℃で10分間、プロペラ撹拌機を用いて650rpmで混合物を撹拌して懸濁液を形成した。TMEDA 4.3mLを加えて重合を実施した。2時間後、撹拌機の速度を400rpmに下げ、そして混合物をさらに16時間撹拌した。酢酸6.6mLを加え、それから10分後、水50mL及び飽和塩化ナトリウム水溶液を加えた。5分後、撹拌機を停止し、そして水相を排出した。ビーズサイズ分別のため、水−ヒドロゲル懸濁液を75、50、40、32及び20μmメッシュのスチール篩上で湿式篩にかけた(wet-sieved)。32、40及び50μmの篩上に残ったビーズ画分を貯め、そして水で3回、エタノールで10回洗浄し、そして0.1mbarで16時間乾燥して白色粉末として3を得た。
Science 9(4): 203-206によって記載されたように、ヒドロゲル上の遊離アミノ基へのfmocアミノ酸の結合、そしてその後のfmoc測定によって決定した。
マレイミド官能化ヒドロゲルビーズ(4)の製造及びマレイミド置換の決定
4−メトキシトリチルクロリド(3g,9.71mmol)をDCM(20mL)中に溶解し、そしてDCM(20mL)中のエチレンジアミン(6.5mL,97.1mmol)の溶液を滴加した。2時間後、溶液をジエチルエーテル(300mL)中に注ぎ、そしてブライン/0.1 M NaOH 30/1(v/v)溶液で3回(それぞれ50ml)、そしてブライン(50mL)で1回洗浄した。有機相をNa2SO4で乾燥し、そして揮発性物質を減圧下で除去してMmt−保護された中間体(3.18g,9.56mmol)を得た。
収量:5.69g(8.09mmol)
MS:m/z 705.4=[M+H]+(MW計算値=705.0)
無水THF(50mL)中の5a(3.19g,4.53mmol)の溶液にBH3・THF(1M溶液,8.5mL,8.5mmol)を加え、そして溶液を室温で16時間撹拌した。さらにBH3・THF(1M溶液,14mL,14mmol)を加え、室温で16時間撹拌した。メタノール(8.5mL)を添加して反応をクエンチし、N,N−ジメチル−エチレンジアミン(3mL,27.2mmol)を加え、そして溶液を還流に加熱し、そして3時間撹拌した。反応混合物を室温に冷却するにまかせ、次いで酢酸エチル(300mL)で希釈し、飽和Na2CO3水溶液(2×100mL)、そして飽和NaHCO3水溶液(2×100mL)で洗浄した。有機相をNa2SO4で乾燥し、そして揮発性物質を減圧で除去して粗アミン中間体(3.22g)を得た。
MS:m/z 791.4=[M+H]+,519.3=[M−Mmt+H]+(MW計算値=791.1)
収量:2.52g(3.19mmol)
MS:m/z 519.3=[M+H]+(MW計算値=518.8g/mol)
中間体5b(985mg,1.9mmol)及びp−ニトロフェニルクロロホルメート(330mg,2.5mmol)を無水THF(10mL)中に溶解した。DIPEA(0.653mL,3.7mmol)を加え、そして混合物を室温で2時間撹拌した。酢酸(1mL)の添加によって溶液を酸性化した。5cをRP−HPLCによって精製した。収量:776mg(1.13mmol)
MS m/z 706.3=[M+Na]+(MW計算値=706.3)
樹脂上の遊離N末端を有する、側鎖が完全に保護されたエキセンジン−4(2.00g,0.2mmol,約0.1mmol/g装填)を、フィルターフリットを備えた20mL注射器に移した。無水DMF 8mLを注射器に吸い込み、そして樹脂を予め膨潤させるため、注射器を15分間振盪(600rpm)させた。溶媒を捨て、そして無水DMF(4mL)中のFmoc−D−アラニン−OH(187mg,0.6mol)、PyBOP(312mg,0.6mmol)、及びDIPEA(174μL,1.0mmol)の溶液を注射器に吸い込んだ。注射器を室温及び600rpmで60分間振盪させた。溶液を排出し、そして樹脂をDMFで10回洗浄した。
“Materials and Methods”に従ってFmoc−脱保護を実施した。
無水DMF(3mL)中の5c(137mg,0.4mmol)の溶液、続いて無水DMF(4.5mL)中のDIPEA(80μL,0.46mmol)の溶液を樹脂6a(0.2mmol)に加え、そして反応混合物を22℃で15時間振盪(600rpm)した。樹脂をDMFで10回、そしてDCMで10回洗浄し、そして真空で乾燥した。
6b(0.05mmol,0.5g)を含む注射器に3−ニトロ−2−ピリジンスルフェニルクロリド(48mg,0.25mmol)を入れた。無水DCM(4mL)を注射器に吸い込み、そして混合物を室温で振盪(600rpm)した。2時間後、溶液を捨て、そして樹脂をDCMで14回洗浄し、そして真空で乾燥した。
丸底フラスコ中で、o−クレゾール(1.5mL)、チオアニソール(1.5mL)、DTT(1.125g)、TES(1.125mL)及び水(1.5mL)をTFA(37.5mL)中に溶解した。均一な懸濁液を得るため、室温で撹拌された(250〜350rpm)溶液に6c(0.15mmol,1.5g)を加えた。撹拌を45分間続けた。濾過によって樹脂ビーズから溶液を分離し、ビーズをTFAで2回(それぞれ2mL)洗浄し、そして洗浄溶液を濾液と合わせた。窒素流れ中で、合わせた溶液からTFAを除去した。
10μmカラム及び40ml/分の流量を用いてMaterials and Methodsに記載されたようにRP−HPLCによって6dを精製した。最大12mLの混合物をカラムに装填した。溶媒B5%から30%までの直線勾配(5分)、続いて溶媒B30%から35%までの直線勾配(40分)を用いて溶離を実施した。生成物6dを含む画分を貯めて凍結乾燥した。
純度:86%(215nm)
収量:85.2mg(19.2μmol,樹脂2.00gから出発)
MS m/z 1486.7=[M+3H]3+,(MW計算値=4460.0g/mol)
エキセンジンリンカー試薬7の合成
収量:13.4mg
MS:m/z 1487.4=[M+3H]3+(MW計算値:4460.0)
エキセンジンリンカーヒドロゲル8の合成
エキセンジン含量30%(質量)を得た。
in vitro放出動態
エキセンジンリンカーヒドロゲル8(0.5mgエキセンジン)のアリコートを、フィルターフリットを備えた注射器に移し、そしてリン酸バッファー(60mM,3mM EDTA,0.01%Tween−20)pH7.4で5回洗浄した。ヒドロゲルを同じバッファー中に懸濁し、そして37℃で定温放置した。所定の時点で(それぞれ定温放置1〜7日後)、上澄みを交換し、そして遊離されたエキセンジンを215nmでRP−HPLCによって定量化した。遊離エキセンジンに関連するUV−シグナルを積分し、そして定温放置時間に対してプロットした。曲線適合ソフトウェアを適用して対応する放出半減期を算定した。半減期45日の一次放出動態を得た(図1参照)。
エキセンジンリンカーヒドロゲル10の合成
遊離N末端を有する樹脂上で側鎖を完全に保護されたリキシセナチド(300mg,約0.1mmol/g装填)を、フィルターフリットを備えた5mL注射器に移した。無水DMF4mLを注射器に吸い込み、そして樹脂を予め膨潤させるため、注射器を15分間振盪(600rpm)させた。溶媒を捨て、そして無水DMF(2mL)中のFmoc−D−アラニン−OH(28mg,90μmol)、PyBOP(47mg,90μmol)、及びDIPEA(26μL,150μmol)の溶液を注射器に吸い込んだ。注射器を室温及び600rpmで60分間振盪させた。溶液を排出し、そして樹脂をDMFで10回洗浄した。
Fmoc−脱保護を、“Materials and Methods”に従って実施した。
無水DMF(1.5mL)中の5c(41mg,60μmol)の溶液を、樹脂11a(30μmol)に加え、続いてDIPEA(13μL,75μmol)を加え、そして均質化された反応混合物を22℃で22時間振盪(600rpm)した。
樹脂をDMFで10回、そしてDCMで10回洗浄し、そして真空で乾燥した。
11bを含む、フィルターフリットを備えた注射器に、3−ニトロ−2−ピリジンスルフェニルクロリド(38mg,0.20mmol)を入れた。無水DCM(2mL)を注射器に吸い込み、そして混合物を室温で振盪(600rpm)した。3.5時間後、溶液を捨て、そして樹脂をDCMで15回洗浄し、そして真空で乾燥した。
50mL−ファルコンチューブ中で、NBu4Br(2.9mg)、チオアニソール(58.3μL)、DTT(170mg)、TES(170μL)、及び水(113.3μL)をTFA(5.83mL)中に溶解した。均一な懸濁液を得るため、室温で撹拌(200rpm)された溶液に11c(30μmol)を加えた。撹拌を1時間続けた。ビーズを濾過し、そしてTFAで2回(各1mL)洗浄した。洗浄溶液を濾液と合わせた。
収量6.1mg
MS:m/z 1284.3=[M+4H]4+(MW計算値=5131.9)
リキシセナチドリンカーヒドロゲル12の合成
リキシセナチドリンカー試薬13の合成
収量7.3mg
MS:m/z 1283.9=[M+4H]4+(MW計算値=5131.9)
リキシセナチドリンカーヒドロゲル14の合成
収量5.0mg
MS:m/z 1191.4=[M+3H]3+(MW計算値=3571.1)
GLP−1リンカーヒドロゲル16の合成
in vitro放出動態
pH7.4、37℃での、ヒドロゲル10からエキセンジンの、ヒドロゲル12及び14からリキシセナチドの、並びにヒドロゲル16からGLP−1の放出半減期を実施例9に記載されたように決定した。化合物8、10、12、14及び16の放出動態を図1に示す。
MS:m/z 390.2=[M+H]+(MW計算値=389.6)
収率:0.82g(1.46mmol)
MS:m/z 563.3=[M+H]+(MW計算値=562.8)
収量:579mg(1.34mmol)
MS:m/z 433.3=[M+H]+(MW計算値=432.7)
収量:339mg(0.57mmol)
MS:m/z 598.3=[M+H]+(MW計算値=597.8)
収量1.33mg
MS:m/z 1196.0=[M+3H]3+(MW計算値=3585.1)
GLP−1リンカーヒドロゲル20の合成
AcOH 酢酸
AcOEt 酢酸エチル
Bn ベンジル
Boc t−ブチルオキシカルボニル
DBU 1,3−ジアザビシクロ[5.4.0]ウンデセン
DCC N,N−ジシクロヘキシルカルボジイミド
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン
DMAP ジメチルアミノ−ピリジン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
DTT DLジチオトレイトール
EDC 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
EDTA エチレンジアミン四酢酸
eq 化学量論的当量
EtOH エタノール
Fmoc 9−フルオレニルメトキシカルボニル
HPLC 高性能液体クロマトグラフィ
HOBt N−ヒドロキシベンゾトリアゾール
iPrOH 2−プロパノール
LCMS 質量分析連動液体クロマトグラフィー
Mal 3−マレイミドプロピル
Mal−PEG6−NHS N−(3−マレイミドプロピル)−21−アミノ−4,7,10,13,16,19−ヘキサオキサ−ヘンエイコサン酸NHSエステル
Me メチル
MeOH メタノール
Mmt 4−メトキシトリチル
MS 質量スペクトル/質量分析
MTBE メチルtert.−ブチルエーテル
MW 分子量
NHS N−ヒドロキシスクシンイミド
PEG ポリ(エチレングリコール)
PyBOP ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスフェート
Phth フタルイミド
RP−HPLC 逆相高性能液体クロマトグラフィー
rpm 1分当たりの回転
RT 室温
SEC サイズ排除クロマトグラフィー
TCEP トリス(2−カルボキシエチル)ホスフィン塩酸塩
TES トリエチルシラン
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TMEDA N,N,N',N'−テトラメチルエチレンジアミン
Tris トリス(ヒドロキシメチル)アミノメタン
Trt トリフェニルメチル、トリチル
UPLC 超高性能液体クロマトグラフィー
V 体積
Claims (22)
- エキセンジンリンカー複合体D−L[式中、
Dは、エキセンジン部分を表し;そして
−Lは、式(I)
R1は、C1-4アルキルから選ばれ;
R2、R2aは、H及びC1-4アルキルからなる群より独立して選ばれる)
によって表される生物活性のないリンカー部分−L1
(ここにおいて、L1は、1つのL2−Zで置換され、そして場合によりさらに置換されるが、但し、式(I)中のアスタリスクでマークされた水素は、置換基によって置き換えられず、そしてここにおいて、
L2は、単化学結合又はスペーサーであり;そして
Zは、ヒドロゲルである)
である]
を含むプロドラッグ又はその薬学的に許容しうる塩。 - L1がさらに置換されない、請求項1に記載のプロドラッグ。
- R1が−CH3である、請求項1又は2に記載のプロドラッグ。
- L2がC1-20アルキル鎖であり、これは、−O−;及びC(O)N(R3aa)から独立して選ばれる1つ又はそれ以上の基によって場合により中断され;OH;及びC(O)N(R3aaR3aaa)から独立して選ばれる1つ又はそれ以上の基で場合により置換され;そして、ここにおいてR3aa、R3aaaは、H;及びC1-4アルキルからなる群より独立して選ばれる、請求項1〜3のいずれか1項に記載のプロドラッグ。
- ヒドロゲルが、骨格鎖部分で構成されるポリエチレングリコール(PEG)ベースのヒドロゲルである、請求項1〜7のいずれか1項に記載のプロドラッグ。
- 請求項1〜14のいずれか1項に記載のプロドラッグ又はその薬学的に許容しうる塩を少なくとも1つの薬学的に許容しうる賦形剤と共に含んでなる薬学的組成物。
- 薬剤として使用するための請求項1〜14のいずれか1項に記載のプロドラッグ又は請求項15に記載の薬学的組成物。
- エキセンジンによって治療することができる疾患又は障害の治療又は予防方法に使用するための請求項1〜14のいずれか1項に記載のプロドラッグ又は請求項15に記載の薬学的組成物。
- エキセンジン−リンカー試薬D−L*[式中、
Dは、エキセンジン部分を表し;そして
L*は、式(IV)
R1は、C1-4アルキルから選ばれ;
R2、R2aは、H及びC1-4アルキルからなる群より独立して選ばれる)
によって表される生物活性のないリンカー試薬であり、
ここにおいてL*は、1つのL2*で置換され、そして場合によりさらに置換されるが、但し、式(IV)中のアスタリスクでマークされた水素は、置換基によって置き換えられることはなく、そしてここにおいて、
L2*は、L*に連結したスペーサーであり、そしてヒドロゲルに複合するための化学官能基を含む]。 - 請求項1〜14のいずれか1項に記載のプロドラッグの製造方法であって、
(a)マレイミド官能化ヒドロゲル微粒子を含む水性懸濁液を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で、L2*の化学官能基がチオール基を含む請求項17のエキセンジン−リンカー試薬を含む溶液と接触させてエキセンジン−リンカー−ヒドロゲル複合体を生成させる工程;
(b)場合により、工程(a)からのエキセンジン−リンカー−ヒドロゲル複合体を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で34Da〜500Daのチオール含有化合物により処理する工程;
を含む、上記方法。 - 請求項1〜14のいずれか1項に記載のプロドラッグの製造方法であって、
(a)チオール官能化ヒドロゲル微粒子を含む水性懸濁液を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で、L2*の化学官能基がマレイミド基を含む請求項18のエキセンジン−リンカー試薬を含む溶液と接触させてエキセンジン−リンカー−ヒドロゲル複合体を生成させる工程;
(b)場合により、工程(a)からのエキセンジン−リンカー−ヒドロゲル複合体を、pH5.5〜8の緩衝水溶液中、室温から4℃の間の温度で100〜300Daのマレイミド含有化合物により処理する工程;
を含む、上記方法。 - 注射針で注射可能なプロドラッグの製造方法であって、
(a)請求項1〜14のいずれか1項に記載の微粒子形態のプロドラッグを製造する工程;
(b)微粒子を篩分けする工程;
(c)プロドラッグビーズ径25〜80μmを有する画分を選別する工程;
(d)工程(c)のビーズ画分を注射に適した水性緩衝液中に懸濁する工程;
を含む、上記方法。
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