JP5775114B2 - ロミデプシンをベースとする癌の処置 - Google Patents
ロミデプシンをベースとする癌の処置 Download PDFInfo
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- JP5775114B2 JP5775114B2 JP2013127496A JP2013127496A JP5775114B2 JP 5775114 B2 JP5775114 B2 JP 5775114B2 JP 2013127496 A JP2013127496 A JP 2013127496A JP 2013127496 A JP2013127496 A JP 2013127496A JP 5775114 B2 JP5775114 B2 JP 5775114B2
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- romidepsin
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- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- FCFNRCROJUBPLU-DNDCDFAISA-N valinomycin Chemical compound CC(C)[C@@H]1NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC1=O FCFNRCROJUBPLU-DNDCDFAISA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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-
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- A61F13/00—Bandages or dressings; Absorbent pads
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
- A61F13/505—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators with separable parts, e.g. combination of disposable and reusable parts
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- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
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Description
本出願は、米国特許法§119(e)の下、2006年12月29日に出願された、米国仮特許出願第60/882,712号に対する優先権を主張し、この出願は本明細書中で参考として援用される。
ロミデプシン(Romidepsin)は、藤沢薬品工業によってChromobacterium violaceumから単離された天然の生成物である。特許文献1(1995);特許文献2(1990年12月11日発行)(これらの各々は、本明細書に参考として援用される)を参照のこと。ロミデプシンは、4つのアミノ酸残基(D−バリン、D−システイン、デヒドロブチリン(dehydrobutyrine)、およびL−バリン)からなる二環式ペプチドであり、かつ新規な酸(3−ヒドロキシ−7−メルカプト−4−ヘプタン酸)である。ロミデプシンは、アミド結合およびエステル結合の両方を含むデプシペプチドである。発酵を使用するC.violaceumの生成に加えて、ロミデプシンはまた、合成手段または半合成手段によって調製され得る。Kahnらによって報告されたロミデプシンの全合成は、14工程を要し、18%の全体収率でロミデプシンを生じる。非特許文献1を参照のこと。ロミデプシンの構造は、以下に示される:
本発明は、純粋なロミデプシン(特に、ダイマー化、オリゴマー化またはポリマー化したロミデプシンのような夾雑物を含まないロミデプシン)を再現可能に生成しないという認識に基づいている。この認識に基づくと、本発明は、これら夾雑する副生成物のレベルを減少させる条件下で、ロミデプシンを再現可能に調製するためのシステムを提供する。約6.5未満の、より好ましくは、約6.0未満の見かけのpHで、ロミデプシンを生成、精製および/または貯蔵することによって、ダイマー化、オリゴマー化またはポリマー化したロミデプシンの形成が妨げられることが見いだされた。ロミデプシンの精製プロセスにおけるこの改善は、公知のプロセスによって提供されるものより、高い収量のロミデプシンおよび/または高い純度のロミデプシンを可能にする。このような改善は、ヒトにおける使用のための製薬グレードのロミデプシンを調製するのに特に有用である。
特定の官能基および化学用語の定義は、以下でより詳細に記載される。本発明の目的のために、化学元素は、元素周期表(CASバージョン,Handbook of Chemistry and Physics,第75版,表紙の裏側)に従って同定され、そして特定の官能基は、一般に、本明細書に記載されるように定義される。さらに、有機化学の一般原理、ならびに特定の官能部分および反応性は、Organic Chemistry,Thomas Sorrell,University Science Books,Sausalito,1999(その全体は、本明細書に参考として援用される)に記載される。
「酸」:用語「酸」は、本明細書で使用される場合、無機酸および有機酸をいう。無機酸の例としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、およびリン酸が挙げられるが、これらに限定されない。有機酸の例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、およびp−トルエンスルホン酸が挙げられるが、これらに限定されない。任意の酸が、上記緩衝剤またはロミデプシンの溶液またはロミデプシンの精製において使用されるもののpHを調節するために使用され得る。特定の実施形態において、酢酸が使用される。特定の実施形態において、塩酸が使用される。特定の実施形態において、クエン酸が使用される。特定の実施形態において、硫酸が使用される。
本発明はまた、以下の項目を提供する。
(項目1)
薬学的組成物であって、該薬学的組成物は、
ロミデプシン;および
薬学的に受容可能な賦形剤
を含み、ここで該ロミデプシンのうちの少なくとも98%は、モノマー性である、薬学的組成物。
(項目2)
上記ロミデプシンのうちの少なくとも99%は、モノマー性である、項目1に記載の薬学的組成物。
(項目3)
上記ロミデプシンのうちの少なくとも99.5%は、モノマー性である、項目1に記載の薬学的組成物。
(項目4)
上記ロミデプシンのうちの少なくとも99.95%は、モノマー性である、項目1に記載の薬学的組成物。
(項目5)
上記組成物は、ダイマー化、オリゴマー化またはポリマー化したロミデプシンを実質的に含まない、項目1に記載の薬学的組成物。
(項目6)
上記組成物は、1.0%以下の総不純物および0.2%以下の個々の不純物を含む、項目1に記載の薬学的組成物。
(項目7)
上記組成物は、新生物を処置するために有効な量のロミデプシンを含む、項目1に記載の薬学的組成物。
(項目8)
上記新生物は癌である、項目7に記載の薬学的組成物。
(項目9)
上記新生物は、血液性悪性疾患である、項目7に記載の薬学的組成物。
(項目10)
上記新生物は、白血病またはリンパ腫である、項目7に記載の薬学的組成物。
(項目11)
上記新生物は、ホジキンリンパ腫である、項目7に記載の薬学的組成物。
(項目12)
上記新生物は、非ホジキンリンパ腫である、項目7に記載の薬学的組成物。
(項目13)
上記新生物は、多発性骨髄腫である、項目7に記載の薬学的組成物。
(項目14)
上記新生物は、皮膚性T細胞リンパ腫である、項目7に記載の薬学的組成物。
(項目15)
上記新生物は、末梢性T細胞リンパ腫である、項目7に記載の薬学的組成物。
(項目16)
上記新生物は、慢性リンパ性白血病(CLL)である、項目7に記載の薬学的組成物。
(項目17)
上記新生物は、慢性骨髄性白血病(CML)である、項目7に記載の薬学的組成物。
(項目18)
上記新生物は、急性骨髄性白血病(AML)である、項目7に記載の薬学的組成物。
(項目19)
上記新生物は、骨髄異形成症候群である、項目7に記載の薬学的組成物。
(項目20)
上記新生物は膵臓癌である、項目7に記載の薬学的組成物。
(項目21)
上記新生物は前立腺癌である、項目7に記載の薬学的組成物。
(項目22)
上記組成物は、1〜56mgのロミデプシンを含む、項目1に記載の薬学的組成物。
(項目23)
経口投与のために処方されている、項目1に記載の薬学的組成物。
(項目24)
非経口投与のために処方されている、項目1に記載の薬学的組成物。
(項目25)
静脈内投与のために処方されている、項目1に記載の薬学的組成物。
(項目26)
別の細胞傷害性薬剤をさらに含む、項目1に記載の薬学的組成物。
(項目27)
上記細胞傷害性薬剤は、ゲムシタビンまたはデシタビンである、項目26に記載の薬学的組成物。
(項目28)
上記細胞傷害性薬剤は、フラボピリドールである、項目26に記載の薬学的組成物。
(項目29)
抗炎症剤をさらに含む、項目1に記載の薬学的組成物。
(項目30)
鎮痛剤をさらに含む、項目1に記載の薬学的組成物。
(項目31)
制吐剤をさらに含む、項目1に記載の薬学的組成物。
(項目32)
解熱剤をさらに含む、項目1に記載の薬学的組成物。
(項目33)
電解質補充物をさらに含む、項目1に記載の薬学的組成物。
(項目34)
カリウム補充物をさらに含む、項目1に記載の薬学的組成物。
(項目35)
マグネシウム補充物をさらに含む、項目1に記載の薬学的組成物。
(項目36)
不整脈治療剤をさらに含む、項目1に記載の薬学的組成物。
(項目37)
血小板ブースターをさらに含む、項目1に記載の薬学的組成物。
(項目38)
エリスロポエチンをさらに含む、項目1に記載の薬学的組成物。
(項目39)
抗高血糖剤(anti−hyperglycemic agent)をさらに含む、項目1に記載の薬学的組成物。
(項目40)
ステロイド剤をさらに含む、項目1に記載の薬学的組成物。
(項目41)
上記ステロイド剤はデキサメタゾンである、項目40に記載の薬学的組成物。
(項目42)
上記組成物は、ロミデプシン以外には、別のHDACインヒビターを含まない、項目1に記載の薬学的組成物。
(項目43)
ロミデプシンの薬学的組成物を調製するための方法であって、該方法は、少なくとも98%の純度のロミデプシンと薬学的に受容可能な賦形剤とを組み合わせる工程を包含する、方法。
(項目44)
項目1〜42のいずれか1項に記載の、少なくとも1種の薬学的組成物および該組成物を投与するための指示書を含む、キット。
本発明は、ロミデプシン(癌の処置において有用な公知のヒストンデアセチラーゼ(HDAC)インヒビター)を調製するための改善されたシステムを提供する。不運なことに、ロミデプシンを調製するための公開された方法は、純粋な、モノマー性のロミデプシンを再現可能に精製しない。驚くべきことに、上記精製プロセスの間のpH制御は、純粋なモノマー性のロミデプシンを再現可能に提供することが見いだされた。特に、低下した見かけのpH(例えば、4〜6の範囲に及ぶ見かけのpH)で上記精製の少なくとも特定の部分を行うことは、ダイマー化、オリゴマー化、またはポリマー化した副生成物が夾雑することなく、精製されたモノマー性のロミデプシンのより高い収量を生じる。
mは、1、2、3もしくは4であり;
nは、0、1、2もしくは3であり;
pおよびqは、独立して、1もしくは2であり;
Xは、O、NH、もしくはNR8であり;
R1、R2、およびR3は、独立して、水素;置換されていないかもしくは置換されている、分枝状もしくは非分枝状の、環式もしくは非環式の脂肪族;不飽和もしくは飽和の、分枝状もしくは非分枝状の、環式もしくは非環式のヘテロ脂肪族;置換されているかもしくは置換されていないアリール;または置換されていないかもしくは置換されているヘテロアリールであり;
R4、R5、R6、R7およびR8は、独立して、水素;または置換されているかもしくは置換されていない、分枝状もしくは非分枝状の、環式もしくは非環式の脂肪族;およびその薬学的に受容可能な塩である。特定の実施形態において、mは1である。特定の実施形態において、nは1である。特定の実施形態において、pは1である。特定の実施形態において、qは1である。特定の実施形態において、XはOである。特定の実施形態において、R1、R2、およびR3は、置換されていないかもしくは置換されている、分枝状もしくは非分枝状の、非環式脂肪族である。特定の実施形態において、R4、R5、R6、およびR7は、すべて水素である。
mは、1、2、3もしくは4であり;
nは、0、1、2もしくは3であり;
qは、2もしくは3であり;
Xは、O、NH、もしくはNR8であり;
Yは、OR8もしくはSR8であり;
R2およびR3は、独立して、水素;置換されていないかもしくは置換されている、分枝状もしくは非分枝状の、環式もしくは非環式の脂肪族;置換されていないかもしくは置換されている、分枝状もしくは非分枝状の、環式もしくは非環式のヘテロ脂肪族;置換されていないかもしくは置換されているアリール;または置換されていないかもしくは置換されているヘテロアリールであり;
R4、R5、R6、R7およびR8は、水素;または置換されているかもしくは置換されていない、分枝状もしくは非分枝状の、環式もしくは非環式の脂肪族;およびその薬学的に受容可能な塩から独立して選択される。特定の実施形態において、mは1である。特定の実施形態において、nは1である。特定の実施形態において、qは2である。特定の実施形態において、XはOである。他の実施形態において、XはNHである。特定の実施形態において、R2およびR3は、置換されていないかもしくは置換されている、分枝状もしくは非分枝状の、非環式の脂肪族である。特定の実施形態において、R4、R5、R6およびR7は、すべて水素である。
本明細書に記載されるように調製されたロミデプシンは、インビトロまたはインビボで使用され得る。上記ロミデプシンは、新生物のインビボでの処置において特に有用である。しかし、上記組み合わせはまた、研究目的または臨床目的で(例えば、ロミデプシンに対する患者の疾患の感受性を決定するために)インビトロで使用され得る。特定の実施形態において、上記新生物は、良性の新生物である。他の実施形態において、上記新生物は、悪性の新生物である。任意の癌が、ロミデプシンを用いて、単独で、もしくは別の薬剤と組み合わせて、処置され得る。
本発明はまた、本明細書に記載されるように調製されたロミデプシンを含む薬学的組成物を提供する。特定の実施形態において、上記組成物は、新生物細胞(例えば、血液の悪性疾患)に対する細胞増殖抑制性活性または細胞傷害性活性を示す。ロミデプシンの例示的投与は、上記に記載される。特定の実施形態において、上記薬学的組成物は、上記薬物の1用量についてのロミデプシンの量を含む。本発明の他の薬学的組成物は、ロミデプシンの複数の用量(例えば、サイクルもしくは全体の処置レジメンを完了するために必要とされる用量の総数)を含み得る。特定の実施形態において、投与されるロミデプシンの量は、上記被験体の血流において細胞傷害性レベル(例えば、ナノモルレベル)を達成するに十分である。特定の実施形態において、上記投与される量は、上記被験体における癌の部位において、ロミデプシンの細胞傷害性濃度(例えば、ナノモルレベル)を達成するに十分である。
SeriesのT.Higuchi and V.Stella,Pro−drugs
as Novel Delivery Systems,Vol.14、およびEdward B.Roche,編,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987(これらはともに、本明細書に参考として援用される)において提供される。
(吸着樹脂によるロミデプシンの精製)
約400gのロミデプシンを含むChromobacterium violaceumの培養ブロス(約600L;H2SO4でpH2.5に調節される)を抽出し、その抽出ブロスを、Sepabeads SP850(非イオン性吸着樹脂)を充填したカラムに適用する。ロミデプシン(せいぜい6g−ロミデプシン/L−樹脂)を、せいぜいsv=6の流速で、上記樹脂に結合させる。水道水(約3倍樹脂容積)および25% アセトン水溶液(約5倍樹脂容積)で洗浄した後、約65% アセトン水溶液およびせいぜいsv=4の流速で溶出を行う。
上記溶出液を水で希釈して、水溶液を生成する(約75% 水分含有量)。この溶液を、Diaion HP20SSカラムに適用する。この非イオン性吸着樹脂は、せいぜいsv=5の流速でロミデプシンを吸着する(約10g−ロミデプシン/L−樹脂)。25% アセトン水溶液(約0.5倍樹脂容積)および40% アセトン水溶液(約4倍樹脂容積)で洗浄した後、47% アセトン水溶液で溶出を行う。上記溶出液を、逆相HPLC(RP−HPLC)によって分析する。その活性画分を、中間保持タンクの中で合わせる。
上記HP20SSカラムから得られる溶出液を水で希釈して、水溶液(約80% 水分含有量)を生成する。この溶液をDiaion HP20カラムに適用する。20% アセトン水溶液で洗浄した後、アセトンで溶出を行う。この溶出液を真空中で濃縮する。上記濃縮物に酢酸エチルを添加した後、上記濃縮物を、真空中でさらに濃縮する。この工程を反復して行う。
得られた濃縮物を酢酸エチル中に溶解し(約6mg/mL)、アルミナ樹脂カラムに適用する(約75g−ロミデプシン/L−樹脂)。上記カラムを酢酸エチル(約2倍アルミナ容積)、およびアセトンと酢酸エチルとの混合物(0.5〜2.0 v/v、約8倍アルミナ容積)で展開する。上記濃縮物にアセチルを添加した後、得られた溶液をさらに濃縮する。
上記工程から得られる濃縮物をメタノールで希釈し、真空中で濃縮して、粗製ロミデプシン結晶を生じる。沈澱した結晶を、濾過により集める。
上記粗製ロミデプシン結晶を、85% アセトン水溶液中に溶解し(約13L/kg−粗製ロミデプシン結晶)、そして攪拌しながら精製水をゆっくりと添加することによって沈澱させる(約65L/kg−粗製ロミデプシン結晶)。上記沈澱した結晶を濾過により集め、15% アセトン水溶液で洗浄する(約5L/kg−粗製ロミデプシン)。上記湿っている結晶を、−70℃未満において真空下で乾燥させる。
前述は、本発明の特定の非限定的な好ましい実施形態を記載してきた。当業者は、単なる慣用的実験を用いて、本明細書に記載される、本発明の具体的実施形態に対する多くの等価物を認識するかまたは確認することができる。当業者は、この記載に対する種々の変更および改変を認識し、これらの変更および改変は、以下の特許請求の範囲において規定される本発明の趣旨からも範囲からも逸脱することなく行われ得る。
Claims (20)
- ロミデプシンを調製する方法であって、該方法は、
Chromobacterium violaceumの発酵ブロスからロミデプシンを単離する工程と、
ロミデプシンを精製する工程と
を含み、該精製工程の少なくとも一部が、4.0〜6.0の範囲の見かけのpHで行われる、方法。 - 前記精製工程は、バッチクロマトグラフィー、カラムクロマトグラフィー、再結晶化、またはそれらの組み合わせによって精製することを含む、請求項1に記載の方法。
- ロミデプシンを調製する方法であって、該方法は、
ロミデプシンを産生するChromobacterium violaceumを発酵させる工程と、
発酵ブロスからロミデプシンを単離する工程と、
ロミデプシンを精製する工程と
を含み、該精製工程の少なくとも一部が、4.0〜6.0の範囲の見かけのpHで行われる、方法。 - 前記精製工程は、ロミデプシンをカラムクロマトグラフィーによって精製することを含む、請求項3に記載の方法。
- 前記精製工程は、ロミデプシンを再結晶化によって精製することを含む、請求項3に記載の方法。
- ロミデプシンを調製する方法であって、該方法は、
ロミデプシンを産生するChromobacterium violaceumを発酵させる工程と、
発酵ブロスからロミデプシンを単離する工程と、
カラムクロマトグラフィーによってロミデプシンを精製する工程と、
ロミデプシンを再結晶化する工程と
を含み、該精製工程または再結晶化工程は、4.0〜6.0の範囲の見かけのpHで行われる、方法。 - 前記精製工程は、非イオン性吸着樹脂を使用してロミデプシンを精製することを含む、請求項6に記載の方法。
- 前記精製工程は、スチレンジビニルベンゼン樹脂を使用してロミデプシンを精製することを含み、該スチレンジビニルベンゼン樹脂は、マクロ多孔性ポリマー疎水性スチレン−ジビニルベンゼン樹脂、多孔性ポリスチレンポリマー樹脂、または非極性コポリマースチレン−ジビニルベンゼン吸着樹脂から選択される、請求項6に記載の方法。
- 前記精製工程は、アルミナを使用してロミデプシンを精製することを含む、請求項6に記載の方法。
- 前記精製工程は、マクロ多孔性ポリマー疎水性スチレンジビニルベンゼン樹脂のカラムまたはバッチを用いるカラムクロマトグラフィーによって、その後多孔性ポリスチレンポリマー樹脂のカラムによって、その後非極性コポリマースチレンジビニルベンゼン吸着樹脂のカラムによって、そしてその後アルミナのカラムによって、ロミデプシンを精製することを含む、請求項6に記載の方法。
- 前記再結晶化工程は、メタノールを使用してロミデプシンを再結晶化することを含む、請求項6に記載の方法。
- 前記再結晶化工程は、85%アセトン水溶液を使用してロミデプシンを再結晶化することを含む、請求項6に記載の方法。
- ロミデプシンを調製する方法であって、
ロミデプシンを産生するChromobacterium violaceumを発酵させる工程と、
発酵ブロスからロミデプシンを単離する工程と、
ロミデプシンを精製する工程と
を含み、該精製工程は、85%アセトン水溶液からのロミデプシンの再結晶化を含み、該85%アセトン水溶液の見かけのpHは、4.0〜6.0に調整される、方法。 - 前記見かけのpHは有機酸を使用して調整される、請求項1、3、6または13のいずれか1項に記載の方法。
- 前記有機酸が酢酸である、請求項14に記載の方法。
- ロミデプシンが98%超モノマー性である、請求項1、3、6または13に記載の方法。
- ロミデプシンが99%超モノマー性である、請求項16に記載の方法。
- ロミデプシンが99.5%超モノマー性である、請求項17に記載の方法。
- ロミデプシンが99.95%超モノマー性である、請求項18に記載の方法。
- ロミデプシンを製造する方法であって、該方法は:
1)ロミデプシンを生成するChromobacterium violaceumを発酵させる工程;
2)ロミデプシンを発酵ブロスから単離する工程;および
3)ロミデプシンを精製する工程;
を包含し、ここで該精製する工程の少なくとも一部は、4.0〜6.0の範囲に及ぶ見かけのpHにおいて行われ、かつロミデプシンは、98%より多くがモノマー性である、方法。
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2007
- 2007-12-28 EP EP07870042A patent/EP2124990A4/en not_active Withdrawn
- 2007-12-28 AU AU2007342030A patent/AU2007342030B2/en not_active Ceased
- 2007-12-28 EP EP14171201.8A patent/EP2815761A1/en not_active Withdrawn
- 2007-12-28 CN CN200780051928A patent/CN101687010A/zh active Pending
- 2007-12-28 MX MX2009006966A patent/MX2009006966A/es not_active Application Discontinuation
- 2007-12-28 WO PCT/US2007/089070 patent/WO2008083290A1/en active Search and Examination
- 2007-12-28 CN CN201310294226.2A patent/CN103497238A/zh active Pending
- 2007-12-28 CA CA002674313A patent/CA2674313A1/en not_active Abandoned
- 2007-12-28 JP JP2009544293A patent/JP2010514802A/ja active Pending
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2013
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EP2124990A4 (en) | 2010-04-21 |
US20100093610A1 (en) | 2010-04-15 |
AU2007342030A1 (en) | 2008-07-10 |
CN101687010A (zh) | 2010-03-31 |
JP2010514802A (ja) | 2010-05-06 |
CN103497238A (zh) | 2014-01-08 |
JP2013240332A (ja) | 2013-12-05 |
WO2008083290A1 (en) | 2008-07-10 |
EP2450049A1 (en) | 2012-05-09 |
EP2815761A1 (en) | 2014-12-24 |
EP2124990A1 (en) | 2009-12-02 |
US20130236928A1 (en) | 2013-09-12 |
BRPI0720734A2 (pt) | 2014-01-07 |
EP2556838A1 (en) | 2013-02-13 |
AU2007342030B2 (en) | 2013-08-15 |
CA2674313A1 (en) | 2008-07-10 |
MX2009006966A (es) | 2009-12-09 |
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