JP2016034958A - 安定mia/cd−rap製剤 - Google Patents
安定mia/cd−rap製剤 Download PDFInfo
- Publication number
- JP2016034958A JP2016034958A JP2015178485A JP2015178485A JP2016034958A JP 2016034958 A JP2016034958 A JP 2016034958A JP 2015178485 A JP2015178485 A JP 2015178485A JP 2015178485 A JP2015178485 A JP 2015178485A JP 2016034958 A JP2016034958 A JP 2016034958A
- Authority
- JP
- Japan
- Prior art keywords
- rap
- formulation
- protein
- histidine
- arginine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
【解決手段】少なくとも5mg/mLのCD−RAPと、グリシン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸又はそれらの塩から選択され、荷電アミノ酸とを備え、前記アミノ酸は、その濃度が1〜8w/v%であり、緩衝剤、浸透圧修飾剤、安定剤、及び賦形剤を更に含みpH6〜8において正味電荷を有する安定水性製剤。前記製剤の成分が、繰り返しの凍結融解に対する安定性を付与する安定水性製剤。前記製剤は、炎症性疾患、好ましくは骨関節炎の治療に用いるためのものである。更に、前記製剤を備えたキット。
【選択図】なし
Description
は、製剤のタンパク質が他の吸着されたタンパク質と共に凝集し、沈殿することで起こり得る。
GPMPKLADRKLCADQECSHPISMAVALQDYMAPDCRFLTIHRGQVVYVFSKLKGRGRLFWGGSVQGDYYGDLAARLGYFPSSIVREDQTLKPGKVDVKTDKWDFYCQ
ジェネリック配列1(配列番号2)
C X4 C X17 C X12 V X 11-13W X7-18 F X4V X21 C X
ジェネリック配列2(配列番号3)
K X C XD X E CX11 D X3 P D C X12 V X2 K LX7-9W X G S X5-13 G Y F P X3
V X18DF X C X
ジェネリック配列3(配列番号4)
K X C XD X2C X8 A X2 D X3 P D C R F X5G X V X5K L X7 W X G S V X12 G Y F P X22
D F X CQ
それぞれ独立して現れる「X」は、アミノ酸のいずれかを表し、下付きの数字は、アミノ酸の数を示す。好ましくは、「X」は、自然発生のアミノ酸、特にA、R、N、D、C、Q、E、G、H、I、L、K、M、F、P、S、T、W、Y又はVを表す。「X」は、ランチオニン、2−アミノイソブチル酸、デヒドロアラニン、オルニチン、シトルリン、ベータアラニン又はノルロイシン等の非標準のアミノ酸をも意味し得る。当然に、本技術分野において一般に知られている翻訳後の修飾は予想される。従って、本発明のCD-RAPポリペプチドは、翻訳後に修飾され得る。ソブチル酸、デヒドロアラニン、オルニチン、シトルリン、ベータアラニン又はノルロイシン等の非標準のアミノ酸をも意味し得る。当然に、本技術分野において一般に知られている本発明の製剤におけるアライメントされたCD-RAPタンパク質は、原核又は真核宿主細胞における未変化又は切断されたゲノムDNA、cDNA又は合成DNAから発現され得る。タンパク質は、培養培地又は封入小体から単離され得る、及び/又は生物活性成分を生成するために再び折り畳まれ得る。CD-RAPの組換えタンパク質の精製のプロトコールの例としては、例えばEP-B1710248及びLougheed等. (2001), Proc.Natl. Acad. Sci. U.S.A98: 5515-5520を参照できる。そのように単離されたタンパク質の活性(例えば軟骨形成)を試験する方法の詳細な説明は、Tscheudschilsuren等. (2005), Exp. Cell Res.1-10; 又はStoll等.(2003), ProteinSci. 12: 510-519に記載されている。軟骨誘導のためのバイオ試験は、EP-B11 146 897の実施例2〜5に記載されている。さらに、バイオ試験は、以下に記載され、また、実施例7及び8に記載されている。
mg/mLの濃度で含まれない。
が約6と8との間で正味電荷を有する。
ソルベート20)等の非イオン性界面活性剤、ポロキサマー(例えばポロキサマ−188)、Triton、ドデシル硫酸ナトリウム(SDS)、ラウリル硫酸ナトリウム、オクチルグリコシドナトリウム、ラウリルスルホベタイン、ミリスチルスルホベタイン、リノレイルスルホベタイン、ステアリルスルホベタイン、ラウリルサルコシン、ミリスチルサルコシン、リノレイルサルコシン、ステアリルサルコシン、リノレイルベタイン、ミリスチルベタイン、セチルベタイン、ラウロアミドプロピルベタイン、コカミドプロピルベタイン、リノレアミドプロピルメライン、ミリストアミドプロピルベタイン、パルミドプロピルベタイン、イソステアラミドプロピルベタイン(例えばラウロアミドプロピル)、ミリスタニドプロピル−、パルミドプロピル−若しくはイソステアラミドプロピル−ジメチルアミン、メチルココイルタウリンナトリウム若しくはメチルオフェイルタウリンジナトリウム、並びにMonaquat シリーズ(Mona Industries, Inc., Paterson,NJ.)、ポリエチレングリコール、ポリプロピルグリコール、及びエチレンとプロピレングリコールとのコポリマー(例えばプルロニック、PF68)を含む。加えられる界面活性剤の量は、高分子量(HMW)の種又は低分子量(LMW)の種の割合を測定するために、例えばSEC-HPLCを用いて試験される再構成されたタンパク質の凝集を許容可能なレベルに維持し、本明細書に記載されているタンパク質製剤の凍結乾燥物の再構成後の微粒子の形成を最小となるように決める。例えば、界面活性剤は、製剤中に、約0.001から約0.5%まで、例えば約0.05から約0.3%までで存在し得る。本発明の製剤に適用されるのに好ましい界面活性剤は、ポリソルベート20又は80である。
可能な抗酸化剤は興味深い。そのような抗酸化剤は、非限定的に、還元剤、アスコルビン酸(ビタミンC)、リポ酸、メラトニン、尿酸、カロテン、レチノール、例えばα−トコフェロール(ビタミンE)であるトコフェロール及びトコトリエノール、並びにユビキノン(声ん財務Q)等を含む。
のインジェクションペン、並びにMediJector及びBioJector等の針を有さない器具を用いた投与に適する。その医薬組成物は、まだ発見されていない投与方法にも適用され得る。Langer, 1990, Science, 249: 1527-1533を参照できる。
1.少なくとも5mg/mLのCD-RAPと、荷電アミノ酸とを備え、前記CD-RAPタンパク質が直接に溶解されている安定水性製剤。
2.前記1.の製剤において、前記アミノ酸は、pH6から8までにおいて正味電荷を有する製剤。
3.前記1.又は2.の製剤において、緩衝剤をさらに備えている製剤。
4.前記1.〜3.のいずれかの製剤において、浸透圧修飾剤をさらに備えている製剤。
5.前記1.〜4.のいずれかの製剤において、安定剤をさらに備えている製剤。
6.前記1.〜5.のいずれかの製剤において、賦形剤をさらに備えている製剤。
7.前記1.〜6.のいずれかの製剤において、pH6から8までである製剤。
8.前記1.の製剤において、 前記荷電アミノ酸は、アルギニン、ヒスチジン、リジン及びグルタミン酸からなる群から選択される製剤。
9.前記1.〜8.のいずれかの製剤において、凍結乾燥(freeze dried, lyophilized)又はスプレードライされ得る製剤。
10.前記1.〜9.のいずれかの製剤において、前記製剤の成分により繰り返しの凍結融解サイクルに対する安定性が付与されている製剤。
11.前記1.〜10.のいずれかの製剤において、治療に用いるための製剤。
12.前記1.〜11.のいずれかの製剤において、炎症性疾患、好ましくは骨関節炎の治療に用いるための製剤。
13.前記1.〜12.のいずれかの製剤を備えているキット。
14.前記1.〜13.のいずれかの製剤において、少なくとも30 mg/mL のCD-RAPを備え、前記緩衝剤は、リン酸カリウム、Tris塩化物、ヒスチジン、アルギニン及びグルタミン酸塩からなる群から選択され、前記アミノ酸は、アスパラギン酸塩、グルタミン酸塩(好ましくはグルタメートリン酸塩)、アルギニン(好ましくはアルギニンリン酸塩又はアルギニン塩化物)、ヒスチジン(好ましくはヒスチジン塩化物又はヒスチジンリン酸塩)、リジン及びグリシンからなる群から選択される製剤。
15.前記1.〜14.のいずれかの製剤において、少なくとも30 mg/mL のCD-RAPと、
(i)50mMのTris塩化物及び2.5%のグルタミン酸塩;
(ii)50 mMのヒスチジン及び2.5% (w/v)のグリシン、2.5%(w/v)のグルタミン酸塩若しくは2.5% (w/v)のリジンと;
(iii)300mMのヒスチジン塩化物pH 6.0;
(iv)50 mM、100 mM、200 mM若しくは300mMのヒスチジンリン酸塩pH 6.0;
(v)350mMのアルギニン塩化物pH 6.0;
(vi)350 mMのアルギニンリン酸塩pH 6.0;
(vii)350mMのアルギニンリン酸塩pH 7.4;又は
(viii)300mMのグルタミン酸カリウムpH 6.0とを備えている製剤。
を有するので、どの成分が適するものであるという一例から結論は出せないため、その目的に合う製剤の適当な成分を見出すための実験を行う必要がある。
(実施例)
実施例1:rhCD-RAPのための種々の緩衝剤系の分析
rhCD-RAPは、36の緩衝剤系に対して透析された(緩衝剤は50mM塩化カリウム、50mMヒスチジン塩化物又は50mMTris塩化物、それぞれpH6.0で、各緩衝剤は、0.1% Tween20を含む又は含まないスクロース、マンニトール、グリシン、リジン及びグルタミン酸から選択される安定剤を含む又は含まない)。濾過により30mg/mLにまでrhCD-RAPを透析する物質濃縮するプロセスの間、サンプルは、UV/Visにより分析された。安定製剤は、凍結融解サイクルによりストレスが与えられた。各サイクルの後、サンプルに遠心法を行い、rhCD-RAPはUV/Visにより定量化された。
2.0mlのrhCD-RAPバルク材料(350mMアルギニン/リン酸塩 pH7.4)は、6〜8kDaの分子量のカットオフチューブを用いて、適度に撹拌しながら4℃で24時間、500mLの所望の緩衝剤に対して透析された。16時間後、透析緩衝剤は、500mLの新鮮な緩衝剤に交換された。その結果生じたタンパク質溶液は、更なる分析のために2〜8℃で保存された。
サンプル中のタンパク質量は、13000rcfで5分間、透析されたrhCD-RAPに対して遠心法を行った後に、UV/Visにより測定された。対応するサンプル緩衝剤は、ブランクの減算のために測定された。タンパク質濃度[mg/ml]の算出のために、280nmにおける吸光度及び280nmにおけるrhCD-RAPの特定の吸収率[1.649 mL/(mg*cm)]が用いられた。
透析されたrhCD-RAPは、2mLの遠心濃縮機に移された。遠心ステップ(4000rcf, 4℃)の後、rhCD-RAP溶液の容量を減らした。残存するrhCD-RAP溶液の容量を測定し、rhCD-RAP濃度をUV/Visにより定量化した。
rhCD-RAPの熱安定性を、超低温フリーザーを用いて5℃から−25℃の5回の凍結融解サイクルを行って評価した。冷却及び加熱速度は、1.0℃/minであり、各サイクルの間には15分の等温ステップを行った。そのタンパク質溶液を、分析まで4℃〜8℃で保存した。濃度が30mg/mLの300μlrhCD-RAPを1.5mLPPバイアルの中に移し、上述のように規定された凍結融解ステップによりストレスを与えた。
実施例1の全ての緩衝剤系の安定化効果を測定した。
以下の物質を最終質量が1kgとなり、緩衝剤濃度が50mMになるようにWFIに溶解した。pHは、KOH及びHClをそれぞれ加えることによりpH6.0に調整した。
a)6.8gのリン酸カリウム、12.4gのKClを含み、1.0gのTween80を含まない
b)6.8gのリン酸カリウム、50gのスクロース、4.9gのKClを含み、1.0gのTween80を含まない
c)6.8gのリン酸カリウム、50gのマンニトール、1.0gのTween80を含む及び含まない
d)6.8gのリン酸カリウム、25gのグリシン、1.0gのTween80を含む及び含まない
e)6.8gのリン酸カリウム、25gのグルタミン酸、1.0gのTween80を含む及び含まない
f)6.8gのリン酸カリウム、25gのリジン、1.0gのTween80を含む及び含まない
g)61.0gのアルギニン、リン酸でpH7.4に調整(コントロール)
必要であれば、塩化カリウムにより300〜400mOsm/kgの等張性を調整した。各緩衝剤のモル浸透圧濃度を表1に示す。
表1:リン酸カリウム緩衝剤のモル浸透圧濃度
可溶性増強剤としてのTween80を含める又は含めないで、スクロース、マンニトール、グリシン、グルタミン酸及びリジン等の種々の安定剤とTris塩化物をWFIに溶解し、最終重量を1kgにし、緩衝剤濃度を50mMとした。それぞれ、追加のHClを用いることにより、pH6.0に調整した。
a)6.05gのTris base、9.7gのNaClを含み、1.0gのTween80を含む及び含まない
b)6.05gのTris base、50gのスクロース、3.9gのNaClを含み、1.0gのTween80を含む及び含まない
c)6.05gのTris base、50gのマンニトールを含み、1.0gのTween80を含む及び含まない
d)6.05gのTris base、25gのグリシンを含み、1.0gのTween80を含む及び含まない
e)6.05gのTris base、25gのグルタミン酸を含み、1.0gのTween80を含む及び含まない
f)6.05gのTris base、25gのリジンを含み、1.0gのTween80を含む及び含まない
必要であれば、塩化カリウムにより300〜400mOsm/kgの等張性を調整した。各緩衝剤のモル浸透圧濃度を表2に示す。
表2:Tris緩衝剤のモル浸透圧濃度
可溶性増強剤としてのTween80を含める又は含めないで、スクロース、マンニトール、グリシン、グルタミン酸及びリジン等の種々の安定剤とヒスチジン塩化物(50mM、pH6.0)を他の2つの緩衝剤系における上記と同様の方法を用いて分析した。
a)7.76gのL−ヒスチジン塩化物、12.4gのKClを含み、1.0gのTween80を含む及び含まない
b)7.76gのL−ヒスチジン塩化物、50gのスクロース、4.9gのKClを含み、1.0gのTween80を含む及び含まない
c)7.76gのL−ヒスチジン塩化物、50gのマンニトールを含み、1.0gのTween80を含む及び含まない
d)7.76gのL−ヒスチジン塩化物、25gのグリシンを含み、1.0gのTween80を含む及び含まない
e)7.76gのL−ヒスチジン塩化物、25gのグルタミン酸を含み、1.0gのTween80を含む及び含まない
f)7.76gのL−ヒスチジン塩化物、25gのリジンを含み、1.0gのTween80を含む及び含まない
必要であれば、等張性を調整した。最終モル浸透圧濃度を表3に示す。
表3:ヒスチジン塩化物緩衝剤のモル浸透圧濃度
結論
凝集することなく30mg/mLまで高濃度のタンパク質を提供するCD-RAPの最も良好な結果は、以下の通りであった。それは、a)5%スクロースを含む50mMリン酸カリウム、b)2.5%グルタミン酸を含む50mMTris塩化物、c)2.5%グリシンを含む50mMヒスチジン、d)2.5%グルタミン酸を含む50mMヒスチジン,e)2.5%リジンを含む50mMヒスチジン、f)5%マンニトールを含むヒスチジン、及びg)350mMアルギニンリン酸塩である。
実施例1では、pH6.0で30mg/mLまでのrhCD-RAPのための7つの緩衝剤の形態を評価した。これらの緩衝剤形態は、ストレス状態、すなわち凍結融解サイクルにおけるrhCD-RAPの安定性の維持について試験された。
実施例2及び3では、アミノ酸を含む緩衝液中の30mg/mLのrhCD-RAPの優れた安定性を示したので、この特別なアミノ酸の効果を以下の実施例で試験した。ヒスチジン及びアルギニン等の塩基性アミノ酸、グリシン等の中性アミノ酸、及びグルタミン酸等の産生アミノ酸に対して、rhCD-RAPの安定化効果についての試験を行った。全てのバルク溶液を、塩又は他の賦形剤の添加なしにpH6.0で等張に調製する。pHを塩酸及びリン酸を用いて調整した。さらに、350mMアルギニンリン酸塩をpH6.0及びpH7.4で試験した。
表4:種々の緩衝剤中で凍結融解サイクルによりストレスが与えられたrhCD-RAP
中性の性質のため、pH6.0の等張グリシン溶液中のrhCD-RAPの乏しい可溶性を実施例4では示した。そこで、本発明者等は、グリシンが非荷電であるがpHの変化に起因するより高い正味電荷及びCD-RAPそれぞれのより高い正味電荷をrhCD-RAPが備える場合のCD-RAPの可溶性の結果を測定した。
上記の実施形態で」は、荷電アミノ酸が、pH6.0等のほぼ中性pHにおいて30mg/mLに達する高濃度のrhCD-RAPの安定化のための優れたツールであることを証明した。同定された緩衝剤の範囲を決定するために、この実施例では、最も適当な例のヒスチジンで、CD-RAPに対する緩衝剤成分の濃度の依存性を示す。従って、以下の表5に示すように0mMから300mMまでの範囲のヒスチジンを含むヒスチジンリン酸塩でrhCD-RAPを透析した。さらに、それらの製剤を、十分な量の塩化カリウムの添加により生理的モル浸透圧濃度に調整した。
表5:L−ヒスチジン緩衝剤の種々の濃度、塩化カリウムを用いて等張状態に調整する前のモル浸透圧濃度
MCHT細胞を96wellプレートに30000cells/wellの濃度で播き、培養培地(10%FCS、グルタミンを含むα-MEM)で一晩培養した。その次の日、rhGDF-5及びrhCD-RAPを用いた刺激を、各ウェルの培養培地を160μlの特定の刺激培地に交換することにより開始した。全ての基準及びサンプルを4つずつ作製した。以下の濃度のrhGDF-5(1200 ng/ml、400ng/ml、133.2 ng/ml、44.5 ng/ml、14.8 ng/mlの完全培養培地中のrhGDF-5)の希釈系列を、検量線の作製のために調製した。rhCD-RAPを介するALP活性の阻害の分析のために、細胞を400ng/mlのrhGDF-5及び1〜10μMのrhCD-RAPを用いて同時刺激した。細胞を刺激培地で3日間培養した後、それらに0.2gのMgCl2x6H2Oを含む2mLのノニデットP40を加えて、インキュベータで16時間インキュベートすることにより溶解した。50μlの溶解物を新しい96wellプレートに移し、50μlの基質緩衝液(0.222gのPNPPを含むジエタノールアミン緩衝液、Pierce社製)を加え、37℃で45分間インキュベートした。その後、0.5MのNaOHを加えることにより反応を停止した。プレートリーダーで405nmの吸光度を測定した。バックグラウンドのALP活性を未処理細胞で測定し、全ての基準及びサンプルから差し引いた。検量線を全てのサンプルにおけるALP活性の算出に用いた。
軟骨を全膝置換の手術を受けている患者に由来するヒトの関節軟骨から単離した。軟骨を骨から切断し、小片に切り分けた。軟骨の小片を、1%ペニシリン/ストレプトマイシンを含み1%プロナーゼを含むDMEM/F12を用いて37℃で1時間消化した。室温で5分間、200×gで遠心法を行った後、軟骨小片をPBSで1回洗浄した。それらを、0.07%のコラゲナーゼAを含む培養培地(10%FCS及び1%ペニシリン/ストレプトマイシンを含むDMEM/F12)を用いて37℃で一晩消化した。その次の日、その細胞懸濁液を、100、70及び40μmのセルストレーナに連続的に通して濾過した。その細胞を遠心沈殿し、培養培地に再建濁し、6wellプレートに250000cells/wellの濃度で播いた。細胞を37℃、5%CO2、90%の湿度で、それらがコンフルエントに達するまで培養した(約1週間)。培地を2日毎に交換した。CD-RAPを用いた刺激のために、細胞を無血清培地で一晩飢餓状態にした。CD-RAP(0.5〜5μM)を無血清培地DMEM/F12に添加し、細胞を24時間培養した。続いて、細胞を溶解し、製造者の説明書に従って、RNeasy Mini Kitを用いてRNAを溶出した。1μgのRNAをQuantiTectReverseTranscription Kit (Qiagen)を用いたcDNAの調製のために用いた。4μlの希釈したcDNA(1:5希釈)、10μlのQuantiFast SYBRGreen PCR Mix (Qiagen)、4μlのヌクレアーゼを含まない水、及び2μlのprimer-mixを用いて、標準条件でLight cyclerを使用した50サイクルの RT-PCRを行った。以下のプライマーを用いた。それは、18SrRNA(Qiagen, QuantiTect Primer AssayQT00199367), MMP13forward GGGTTCCTGATGTGGGTGAATA (配列番号5), MMP13reverse GCCATCGTGA AGTCTGGTA (配列番号6)である。その結果物をハウスキーパー18SrRNAで正規化した。
Claims (15)
- 少なくとも5mg/mLのCD-RAPと、
グリシン、アルギニン、リジン、ヒスチジン、アスパラギン酸、グルタミン酸及びそれらの塩からなる群から選択される荷電アミノ酸とを備え、
前記荷電アミノ酸の濃度が1%〜8%(w/v)であり、前記CD-RAPタンパク質が直接に溶解されている安定水性製剤。 - 前記アミノ酸は、pH6から8までにおいて正味電荷を有する請求項1に記載の製剤。
- 緩衝剤をさらに備えている請求項1又は2に記載の製剤。
- 浸透圧修飾剤をさらに備えている請求項1〜3のいずれか1項に記載の製剤。
- 安定剤をさらに備えている請求項1〜4のいずれか1項に記載の製剤。
- 賦形剤をさらに備えている請求項1〜5のいずれか1項に記載の製剤。
- pH6から8までである請求項1〜6のいずれか1項に記載の製剤。
- 前記荷電アミノ酸は、アルギニン、ヒスチジン、リジン及びグルタミン酸からなる群から選択される請求項1に記載の製剤。
- 凍結乾燥(freeze dried, lyophilized)又はスプレードライされ得る請求項1〜8の
いずれか1項に記載の製剤。 - 前記製剤の成分により繰り返しの凍結融解サイクルに対する安定性が付与されている請求項1〜9のいずれか1項に記載の製剤。
- 治療に用いるための請求項1〜10のいずれか1項に記載の製剤。
- 炎症性疾患の治療に用いるための請求項1〜11のいずれか1項に記載の製剤。
- 請求項1〜12のいずれか1項に記載の製剤を備えているキット。
- 少なくとも30 mg/mL のCD-RAPを備え、
前記緩衝剤は、リン酸カリウム、Tris塩化物、ヒスチジン、アルギニン及びグルタミン酸塩からなる群から選択され、
前記アミノ酸は、アスパラギン酸塩、グルタミン酸塩、アルギニン、ヒスチジン、リジン及びグリシンからなる群から選択される請求項3〜7及び9〜13のいずれか1項に記載の製剤。 - 少なくとも30 mg/mL のCD-RAPと、
(i)50mMのTris塩化物及び2.5%のグルタミン酸塩;
(ii)50 mMのヒスチジン及び2.5%(w/v)のグリシン、2.5%(w/v)のグルタミン酸塩若しくは2.5% (w/v)のリジンと;
(iii)300mMのヒスチジン塩化物pH6.0;
(iv)50 mM、100 mM、200 mM若しくは300mMのヒスチジンリン酸塩pH 6.0;
(v)350mMのアルギニン塩化物pH6.0;
(vi)350 mMのアルギニンリン酸塩pH6.0;
(vii)350mMのアルギニンリン酸塩pH7.4;又は
(viii)300mMのグルタミン酸カリウムpH 6.0とを備えている請求項1〜14のいずれか
1項に記載の製剤。
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