JP2022511554A - メイソインジゴの多形体およびメイソインジゴの改変された製剤 - Google Patents
メイソインジゴの多形体およびメイソインジゴの改変された製剤 Download PDFInfo
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Abstract
Description
[001]本出願は2018年12月7日に出願された米国仮特許出願第62/776,965号の優先権を主張し、それは参照によりその全体が本明細書に組み込まれる。
[002]本発明は医薬組成物、より特定的にはメイソインジゴの新規な結晶質(crystalline)形態、調製方法、およびがんを予防し、がんを治療し、またはサイクリン依存性キナーゼの阻害、炎症性サイトカインの発現、もしくは抗炎症性サイトカインの発現低減に関連する炎症関連疾患を治療する方法に関する。
[003]がんの予防および治療は、疫学、治療技術、および早期診断を達成する技量の進歩のため、この10年間米国で著しく向上した。しかしながら、肺、乳房、前立腺、結腸などのような多様ながんの治療法を見出すことは、いまだに大きな課題である。がんの治療のための現在の手法は今でも寿命の延長、またはクオリティーオブライフの上昇に限定されている。加えて、ほとんどの有意義な治療はやはり著しい副作用がある。したがって、副作用がより低いより効果的な治療薬を見出すことが必要不可欠である。
[0012]ある態様において、固体形態または固体結晶形態は実質的に図1に示されているN-メチルイソインジゴの赤外線スペクトルを有する。他の態様において、固体形態または固体結晶形態は実質的に図2に示されているN-メチルイソインジゴのNMRスペクトルを有する。
[0019]ある実施形態において、固体形態または固体結晶形態は少なくとも約90重量%の量で医薬組成物中に存在する。他の実施形態において、固体形態または固体結晶形態は少なくとも約10重量%、少なくとも約20重量%、少なくとも約30重量%、少なくとも約40重量%、少なくとも約50重量%、少なくとも約60重量%、少なくとも約70重量%、少なくとも約80重量%、または少なくとも約90重量%の量で医薬組成物中に存在する。
[0022]ある実施形態において、本発明は本明細書に開示される固体形態または固体結晶形態を調製する方法を提供し、方法は有機溶媒を含む溶液から結晶質形態を沈殿させることを含む。1つの実施形態において、溶液は氷酢酸を含む。別の実施形態において、溶液は更にN-メチルイサチン、オキシインドール、および/またはHClを含む。
[0041]ある実施形態において、固体形態または固体結晶形態は、患者またはそれを必要とする患者に投与されるのに使用される状態にある医薬組成物または製剤の形態である。固体形態または固体結晶形態は、経口、静脈内、局所、局部的据付、腹腔内または経鼻経路により投与され得る。前記組成物はそれを必要とする患者への投与により所望の薬理学的効果を達成するように利用されることができる。
[0046]経口投与の場合、本発明による化合物を、例えば、錠剤(素錠または被覆錠剤、例えば遅延して溶けるかまたは不溶性の腸溶性または制御放出性のコーティングを有するもの)、口腔内崩壊錠剤、フィルム剤/ウエハー剤、フィルム剤/凍結乾燥剤、カプセル剤(例えばハードまたはソフトゼラチンカプセル剤)、糖衣錠剤、顆粒剤、丸剤、散剤、乳剤、懸濁剤、エアゾール剤または液剤のように、本発明の化合物を迅速におよび/または改変されたやり方で送達する当技術分野で公知の投与形態に製剤化することが可能である。本発明による化合物を結晶質および/または非晶質および/または溶解形態で前記投与形態に組み込むことが可能である。
・充填材および担体(例えば、セルロース、微晶質セルロース(microcrystalline cellulose)(例えば、Avicel”)、ラクトース、マンニトール、デンプン、リン酸カルシウム(例えば、Di-Cafos*))、
・軟膏基剤(例えばワセリン、パラフィン、トリグリセリド、ワックス、羊毛脂、ウールワックスアルコール、ラノリン、親水性軟膏、ポリエチレングリコール)、
・座薬用基剤(例えば、ポリエチレングリコール、カカオバター、固い脂肪)、
・溶媒(例えば水、エタノール、イソプロパノール、グリセロール、プロピレングリコール、中鎖トリグリセリド脂肪油、液体ポリエチレングリコール、パラフィン)、
・界面活性剤、乳化剤、分散剤または湿潤剤(例えばドデシル硫酸ナトリウム)、レシチン、リン脂質、脂肪アルコール(例えば、Lanette*)、ソルビタン脂肪酸エステル(例えば、Span”)、ポリオキシエチレンソルビタン脂肪酸エステル(例えば、Tween*)、ポリオキシエチレン脂肪酸グリセリド(例えば、Cremophor*)、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン脂肪アルコールエーテル、グリセロール脂肪酸エステル、ポロクサマー(例えば、Pluronic*)、
・緩衝剤、酸および塩基(例えばホスフェート、カーボネート、クエン酸、酢酸、塩化水素酸、水酸化ナトリウム溶液、炭酸アンモニウム、トロメタモール、トリエタノールアミン)、
・等張化剤(例えばグルコース、塩化ナトリウム)、
・吸着剤(例えば高分散化シリカ)、
・増粘剤、ゲル形成剤、濃厚剤および/または結合剤(例えばポリビニルピロリドン、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピル-セルロース、カルボキシメチルセルロース-ナトリウム、デンプン、カルボマー、ポリアクリル酸(例えば、Carbopol*);アルギネート、ゼラチン)、
・崩壊剤(例えば加工デンプン、カルボキシメチルセルロース-ナトリウム、ナトリウムデンプングリコレート(例えば、Explotab*)、架橋ポリビニルピロリドン、クロスカルメロース-ナトリウム(例えば、AcDiSof))、
・流動調節剤、潤滑剤、流動促進剤および離型剤(例えばステアリン酸マグネシウム、ステアリン酸、タルク、高分散化シリカ(例えば、Aerosil*))、
・コーティング材(例えば砂糖、シェラック)および迅速にまたは改変されたやり方で溶けるフィルムまたは拡散膜用のフィルムフォーマー(例えばポリビニルピロリドン(例えば、Kollidon*)、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、エチルセルロース、ヒドロキシプロピル-メチルセルロースフタレート、セルロースアセテート、セルロースアセテートフタレート、ポリアクリレート、ポリメタクリレート、例えば、Eudragit*))、カプセル材(例えば、ゼラチン、ヒドロキシプロピルメチルセルロース)、
・合成ポリマー(例えばポリラクチド、ポリグリコリド、ポリアクリレート、ポリメタクリレート(例えば、Eudragit*)、ポリビニルピロリドン(例えば、Kollidon*)、ポリビニルアルコール、ポリビニルアセテート、ポリエチレンオキシド、ポリエチレングリコールならびにそれらのコポリマーおよびブロックコポリマー)、可塑剤(例えばポリエチレングリコール、プロピレングリコール、グリセロール、トリアセチン、トリアセチルシトレート、ジブチルフタレート)、浸透促進剤、
・安定剤(例えば酸化防止剤、例えば、アスコルビン酸、アスコルビルパルミテート、アスコルビン酸ナトリウム、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、没食子酸プロピル)、保存料(例えばパラベン、ソルビン酸、チオマーサル、塩化ベンザルコニウム、クロルヘキシジンアセテート、安息香酸ナトリウム)、
・着色剤(例えば無機顔料、例えば、酸化鉄、二酸化チタン)、
・香味料、甘味料、香味-および/または臭気-マスキング剤。
[0053]不規則および/または異常炎症は広範囲のヒトの病気の主要な要素である。多様な変性疾患を患う人々は過剰の血中炎症マーカーレベルを示すことが多い。かかる炎症マーカーの1つのタイプは炎症マーカーサイトカイン、例えばIL-1α、β、IL-2、IL-3、IL-6、IL-7、IL-9、IL-12、IL-17、IL-18、IL-23、TNF-α、LT、LIF、オンコスタチン、およびIFNc1α、β、γである。
[0056]炎症性大腸炎(IBD)はクローン病(CD)および潰瘍性結腸炎(UC)を含み、いずれも世界中の多くの部分で増大する頻度で起こる特発性の慢性病である。米国において、毎年600,000を超える人が侵されている。IBDは小腸および大腸のいずれかまたは両方に関することができる。CDは胃腸管のあらゆる部分に関わることができるが、ほとんどの場合遠位小腸および結腸に関する。それは直腸を使わないか、または直腸の回りにドレナージによる炎症もしくは感染症を引き起こす。UCは通常、多くの場合直腸から始まる大腸の下方部分に潰瘍を生じる。症状は変化するが、下痢、発熱、および痛みを含み得る。UCが長引く患者は結腸がんを発症するリスクが増大する。現在のところ、感染および免疫メカニズムが提案されているがIBDの原因は不明であるので十分な治療法はない。IBD治療は、慣習的に副腎皮質ステロイド、アミノサリチレートおよび標準的な免疫抑制剤、例えばアザチオプリン(6-メルカプトプリン)、メトトレキサートおよびシクロスポリンを用いて炎症症状を制御することを目的とする。もちろん、最良の病態修飾療法は免疫抑制剤:アザチオプリンおよびメトトレキサートであり、いずれも作用の発現が遅く、中程度の効力しかない。長期の治療は肝臓の損傷(線維症または肝硬変)および骨髄抑制を起こし得る。また、患者はかかる治療に不応性になることが多い。他の治療法は単に症状に対処するのみである。
[0058]乾癬はいろいろな形態および様々な重症度レベルで現れる最も一般的な免疫介在性の慢性の皮膚病の1つであり、米国でおよそ2%または450万を超える人々が罹り、そのうちの150万人は中程度~重篤な形態の病気を有すると考えられる。乾癬患者の10~30パーセントはある形態の関節炎、即ち関節付近の骨および結合組織を損傷する乾癬性関節炎も発症する。乾癬は薄片状の白い蓄積により覆われて盛り上がった赤い皮膚の斑点として見える。また、にきびのような(膿疱性乾癬)または焼けた(紅皮症)外観も有し得る。乾癬はまた激しい痒みおよび熱傷も引き起こし得る。患者は心身ともに影響を受ける。現在幾つかのモダリティー、例えば局所治療、光線療法、および全身適用が乾癬の治療に利用可能である。しかし、それらは一般に病気を抑え病気を変性させるのみと考えられる。そしていずれも治癒的ではない。また、多くの治療は美容上望ましくないか、長期の使用に不都合であるか、または有意な毒性を伴う。
[0062]関節リウマチ(RA)は面倒な炎症性障害の別の例である。それは関節および/またはその他の内部器官の内膜(滑膜)の慢性の炎症に特徴付けられる一般的な慢性炎症関連疾患である。炎症性細胞はまた骨および軟骨も侵し損傷することができる。関係する関節はその形状および配列を失うことができ、結果として運動を喪失する。RAの患者は関節の痛み、凝り、火照り、発赤、および腫れ、ならびに発熱、倦怠感、および貧血のような他の全身症状をもつ。現在米国において人口のおよそ1%または210万人が罹っており、女性(150万人)が男性(60万人)より多い。RAの病理は十分理解されていないが、不適切な免疫学的反応のカスケードがメカニズムとして仮定されている。残念ながら従来の治療はRAに効果がない(29)。病気は1950年代以来使用されているコルチコステロイドおよび非ステロイド系抗炎症薬(NSAID)を含む徴候的薬物に完全に応答しない。また、これらの薬物には重大な副作用のリスクもある。メトトレキサート(MTX)のような疾患修飾性抗リウマチ薬(DMARD)の治療効果は一貫性がなく寿命が短いことが多い。
[0066]間質性膀胱炎または痛みを伴う膀胱症候群および慢性前立腺炎または慢性骨盤痛症候群は最近泌尿器慢性骨盤痛症候群(UCPPS)と改名された。UCPPSは軽度の熱傷または不快感から深刻な痛みまでの範囲にわたることができる心地悪い膀胱圧、膀胱痛および/または骨盤痛の組合せにより特徴付けられる慢性の病気である。およそ100万人のアメリカ人が罹る。児童と男性が罹り得るがほとんどが女性である。UCPPSは患者のクオリティーオブライフに対して長く続く不利で著しい影響を有し得る。継続する努力にもかかわらず、有効な治療もUCPPSの発病の機構上の理解も存在しない。
[0071]多発性硬化症(MS)は米国において350,000~500,000の人々で診断される自己免疫疾患である。脳および脊髄においてミエリンの炎症および瘢痕化の多数の領域が病気を示す。MS患者はミエリンの瘢痕化の位置および程度に応じて様々な程度の神経学的機能障害を示す。MSの共通の症状には倦怠感、虚弱、痙性、平衡障害、膀胱および腸管障害、無感覚、失明、震え、および憂鬱がある。MSの現在の治療法は単に症状を緩和するかまたは身体障害の進行を遅らせるのみであり、幹細胞移植および遺伝子療法を含めてMSの幾つかの新しい治療法は温存(conservatory)である。抗-TNF抗体が実験的自己免疫脳脊髄炎(EAE)において保護効果を示してはいるが、MS患者において病気を悪化させ、TNF-α単独の阻害が充分ではないことを示唆している。
[0073]アルツハイマー病(AD)およびパーキンソン病(PD)は2つの最も一般的な神経変性疾患である。ADは脳障害である。それは人の日常活動を行なう能力に深刻な影響を及ぼす。脳の思考、記憶、および言語を司る部分が関与する。通常60歳を超えた約400万のアメリカ人がADにかかると見積もられる。
結晶形Iの調製
[0088]機器および出発材料
[0089]反応容器:製造はサーモウェル、還流冷却器ならびに試薬および溶媒を装入するための口を備えた12リットル丸底フラスコで行なう。
[0091]卓上ろ過用漏斗:内径10.25”(26.035cm)、全高8”(20.32cm)で、固定された多孔質フィルタープレートを含有し、12.7mmの真空接続器を備えた高密度ポリエチレン漏斗。
[0093]主プロセスステップ
[0094]バルクのN-メチルイソインジゴ(Natura-alpha、NAT)の生産のための製造プロセスは次の主ステップを含む。
[0097]3.反応混合物を25~30℃に冷却させ、沈殿した生成物を吸引ろ過する。
[0098]4.フィルターケーキを0.75Lおよび0.38Lの氷酢酸で洗浄し、吸引乾固する。
[00102]N-メチルイソインジゴは暗赤色の結晶質粉末である。N-メチルイソインジゴの融点は235~237℃である。N-メチルイソインジゴはアセトン、クロロホルム、およびエタノールにやや溶け難い。N-メチルイソインジゴは水に難溶性である。
[00105]構造の解明:化合物N-メチルイソインジゴの構造解明および構造が提供される。構造解明に使用された分析技術は赤外分光光度法、核磁気共鳴分析法、および質量分析法である。
[00107]化合物の赤外線スペクトルは無水KBr中化合物の1%混合物のペレットで得られた。1685および1695cm-1のIR吸収は予想生成物のカルボニル吸収の特徴であった。結果は以下図1に提供される。
[00109]核磁気共鳴スペクトルはNuMega Resonance Labs, Inc.(San Diego, CA)により記録された。スペクトルは基準ピークとしてδ 7.27ppmの残留プロトン共鳴を用いて重水素化クロロホルム溶液で得られた;δ 3.29(s、3H)、6.79(d、J=8Hz、1H)、6.81(d、J=8Hz、1H)、7.06(dd、J=8、8Hz、1H)、7.08(dd、J=8、8Hz、1H)、7.31(dd、J=8、8Hz、1H)、7.39(dd、J=8、8Hz、1H)、7.85(bs、1H)、9.12(d、J=8Hz、1H)、および9.19(d、J=8Hz、1H)のプロトン共鳴は予想生成物の構造と一致した。結果は以下図2に提供される。
[00111]質量スペクトルもNuMega Resonance Labs, Inc.により記録された。イオン化はエレクトロスプレーイオン化法を用いることにより達成された。ポジティブQ1スキャン(図3)の277質量単位の陽イオンおよびネガティブQ1スキャン(図4)の275質量単位の陰イオンはそれぞれ予想生成物のM+HおよびM-Hイオンの特徴であった。
[00113]固体状態
[00114]融点
[00115]融点は毛細管型融点装置を用いて得られた。毛細管はO.D.が0.8~1.1mm、長さが90mmで一端でシールされた。融解温度はK-タイプの熱電対を用いて較正された電子温度計で測定された。融解範囲は235℃~237℃、偏差<3℃であった。
[00117]多形研究
[00118]多形のスクリーニング
[00119]X線回折パターンは原薬の4つのバッチNAT-0501、NAT-0502、NAT-0503およびNAT-0601を用いて評価された。
[00121]1.同じ製造手順に由来する4つ全ての試料は、2θ=7.71°の1つのピークが優勢である(約40,000カウントに対して次に高いピークは2,000)同じ結晶形態の化合物を含む。
[00123]3.試料NAT-0601は他より少しだけより結晶質であり、17、18および29°ピークの肩のようにより弱いピークがより多い。
[00126]試料の粉末X線回折パターンにおける特徴的ピークの検索/適合は粉末X線データベース(PDF 2006およびICSD 2007)に公知の相をもたらさなかった。したがって、相の決定はなされ得なかった。しかしながら、(Cambridge構造データベースから得られた)イソインジゴの粉末パターンの外観から分かるように、試料のパターンはイソインジゴのおおよそのサイズおよび配向(結晶単位格子内)の平面の広げられた分子と一致し、これも図7に見られるようにちょうど7.7°に1つの主ピークを、そして13<2θ<30°)にずっと弱いが「指状の」領域を有する。
粒度および分布
[00129]結晶形Iはその粒度および分布について分析された。5つのバッチがMalvern Mastersizer 2000(MIIA14730、Malvern、UK)を用いて試験された。
追加の結晶形態の調製
[00132]いろいろな形態の結晶質のN-メチルイソインジゴ(Natura-alpha)を生成するいろいろな合成経路およびいろいろな結晶化/再結晶化条件を研究した後、本発明者らは以下の合成および結晶化/再結晶化の追加の条件を確認した。得られた生成物はX線粉末回折(XRD)を用いて検査された。
[00141]試料#1~#6の幾つかの物理的性質を表4に示す。これらの結晶形態の外観は異なる:試料#1および#5は粉末様であり;試料#2および#4は樹枝状であり、一方試料#3および#6は針状である。樹枝状および針状はいずれも流動速度が遅いことが知られており、したがって製剤には理想的でない。重要なことに、これら全ての結晶質形態はより低い融点を示し(即ち、結晶形Iに対して上で開示した235.2°~236.6℃と比較して225.4°~229.5℃)、これらの結晶形態が結晶形Iと異なることを示している。
Claims (20)
- 2シータを単位として約7.71°にピークを含むX線粉末回折パターンを有するN-メチルイソインジゴの固体形態またはN-メチルイソインジゴの固体結晶形態(結晶形I)。
- 2シータを単位として約7.71°、約17°、約18°、および約29°にピークを含むX線粉末回折パターンを有する、請求項1に記載の固体形態または固体結晶形態。
- 実質的に図5に示されているX線粉末回折パターンを有する、請求項1または2に記載の固体形態または固体結晶形態。
- 実質的に図1に示されているN-メチルイソインジゴの赤外線スペクトルを有する、請求項1~3のいずれか1項に記載の固体形態または固体結晶形態。
- 実質的に図2に示されているN-メチルイソインジゴのNMRスペクトルを有する、請求項1~4のいずれか1項に記載の固体形態または固体結晶形態。
- 約235℃~237℃に吸熱ピークを含む示差走査熱量測定(DSC)サーモグラムを有する、請求項1~5のいずれか1項に記載の固体形態または固体結晶形態。
- 実質的に表1に示されている示差走査熱量測定(DSC)サーモグラムを有する、請求項1~6のいずれか1項に記載の固体形態または固体結晶形態。
- 25μm未満の平均粒度d50の粒度分布を有する、請求項1~7のいずれか1項に記載の固体形態または固体結晶形態。
- 2.50未満の粒度分布比(d90-d10)/d50および100μm未満の最大粒径を有する、請求項8に記載の固体形態または固体結晶形態。
- 粒度分布が、製剤化の際の製剤加工を容易にし、固体形態または固体結晶形態の安定性およびバイオアベイラビリティを高める、請求項8または9に記載の固体形態または固体結晶形態。
- 請求項1~10のいずれか1項に記載の固体形態または固体結晶形態、および薬学的に許容される担体を含む医薬組成物。
- 固体形態または固体結晶形態が少なくとも約90重量%の量で前記組成物中に存在する、請求項11に記載の医薬組成物。
- 実質的に精製されている、請求項1~10のいずれか1項に記載の固体形態または固体結晶形態。
- 結晶質である、請求項1~10のいずれか1項に記載の固体形態または固体結晶形態。
- 請求項1~10のいずれか1項に記載の固体形態または固体結晶形態を調製する方法であって、有機溶媒を含む溶液から結晶質形態を沈殿させるステップを含む、方法。
- 溶液が氷酢酸を含む、請求項15に記載の方法。
- 溶液が更にN-メチルイサチン、オキシインドール、および/またはHClを含む、請求項16に記載の方法。
- 請求項15~17のいずれか1項に記載の方法により調製され、他の任意の許容できる有機溶媒、好ましくは氷酢酸で再結晶されるN-メチルイソインジゴの固体形態または固体結晶形態。
- 請求項1~10のいずれか1項に記載の固体形態もしくは固体結晶形態または請求項11もしくは12に記載の医薬組成物を、それを必要とする患者に投与するステップを含む、がんを治療する方法。
- 請求項1~10のいずれか1項に記載の固体形態もしくは固体結晶形態または請求項11もしくは12に記載の医薬組成物を、それを必要とする患者に投与するステップを含む、サイトカイン発現レベルに関連する炎症関連疾患を治療する方法。
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