JP6472063B2 - 少なくとも1つの炎症性要素を呈する腸管疾患を治療するための方法 - Google Patents
少なくとも1つの炎症性要素を呈する腸管疾患を治療するための方法 Download PDFInfo
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- JP6472063B2 JP6472063B2 JP2017138019A JP2017138019A JP6472063B2 JP 6472063 B2 JP6472063 B2 JP 6472063B2 JP 2017138019 A JP2017138019 A JP 2017138019A JP 2017138019 A JP2017138019 A JP 2017138019A JP 6472063 B2 JP6472063 B2 JP 6472063B2
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Description
本出願は、2012年2月13日に出願した米国特許仮出願第61/598,308号明細書の優先権を主張するものである。この出願は、その全体が本明細書に組み込まれる。
本出願は、特願2014−557019号を基礎とする分割出願である。
別段の定義がない限り、本明細書で使用されるすべての専門用語、表記法、および他の科学用語は、本開示が属する技術分野の当業者に一般に理解される意味を有することが意図される。一部の事例では、一般に理解される意味を有する用語は、明瞭にするためにおよび/または即時の参照のために本明細書で定義されるが、本明細書へのそのような定義の包含は、当技術分野において一般的に理解されるものに対する実質的な相違を表すものと必ずしも解釈されるべきではない。
(1)a)少なくとも1つの炎症性要素を呈する腸管疾患の治療または寛解の維持に有効な量のブデソニドと、
b)少なくとも1種の親油性賦形剤と、
c)少なくとも1種の両親媒性賦形剤と、
d)少なくとも1種の親水性賦形剤と
を含む錠剤コアと、
(2)錠剤コア上のコーティングであって、胃耐性フィルムを含むコーティングと
を含むことを特徴とする医薬も提供される。
第1の組成物は、全身性コルチコステロイドおよび非全身性コルチコステロイドから選択される少なくとも1種の化合物を含み得る。いくつかの実施形態では、第1の組成物は、炎症性腸疾患(IBD)、たとえば、潰瘍性大腸炎またはクローン病を治療するための化合物の用量を含む。化合物は、小分子化合物またはバイオロジック、たとえば、抗体、タンパク質もしくはペプチド、またはRNAもしくはDNAベースの薬物であり得る。
第2の組成物は、ブデソニドを含む錠剤を含み得る。一実施形態では、錠剤は、炎症性腸疾患の治療および/または炎症性腸疾患の寛解の維持に有効な量のブデソニド、たとえば、3mgのブデソニド、4.5mgのブデソニド、6mgのブデソニド、または9mgのブデソニド、または12mgのブデソニド、または15mgのブデソニド、または18mgのブデソニドを含み得る。別の実施形態では、錠剤は、ブデソニドと、少なくとも1種の親油性賦形剤と、少なくとも1種の両親媒性賦形剤と、少なくとも1種の親水性賦形剤とを含み得る。
実施例
下記の実施形態は、当業者に公知の方法を使用して改変して、その各々が約1mgから約20mgのブデソニド、たとえば、約1mgから約12mgのブデソニド、約1mgから約18mgのブデソニド、約18mgのブデソニド、約15mgのブデソニド、約12mgのブデソニド、約9mgのブデソニド、約6mgのブデソニド、約4.5mgのブデソニド、または約3mgのブデソニドを含有する剤形、たとえば錠剤を調製してもよい。
ブデソニドMMX(登録商標)組成物
2.7kgのブデソニド、3.0kgのレシチン(両親媒性賦形剤)、および3.0kgのステアリン酸(親油性賦形剤)を、篩にかけた後、均質な混合物が得られるまで混合する。次いで、39.0kgの不活性な機能性賦形剤および9.0kgの低粘度ヒドロキシプロピルセルロース(結合剤)を加え、10分間混合した後、精製水を加えて好適な粘稠度になるまで混練する。次いで、粒状物(granulate)を、好適なスクリーンを備えた回転式造粒機に通し、粒状物を流動床乾燥機に移して残留水分含量を3%未満まで低下させる。乾燥した粒状物を新たに篩にかけた後、9.0kgのヒドロキシプロピルセルロース(親水性賦形剤)および好適な量の機能性賦形剤(特に、微結晶性セルロース、ラクトース、および二酸化ケイ素)を加え、15分混合した後、潤滑剤として作用する好適な分量のステアリン酸マグネシウムを加える。
ブデソニドMMX(登録商標)組成物
− pH1で2時間後 耐性(<5%)
− pH6.4で1時間後 耐性(<5%)
− pH7.2で2時間後 15%
− pH7.2で4時間後 37%
− pH7.2で8時間後 91%
ブデソニドMMX(登録商標)組成物
9mgのブデソニドを含み以下の組成を有する、個々の重量が約330mgである錠剤を調製した。
ブデソニドMMX(登録商標)組成物
6mgのブデソニドを含み以下の組成を有する、個々の重量が約330mgである錠剤を調製した。
ブデソニドMMX(登録商標)組成物
ブデソニド(3.0kg)を大豆レシチン(5.0kg)と均質な混合物が得られるまで混合する。次いで、細目スクリーンを通して篩にかけたカルナウバワックス(2.0kg)およびステアリン酸(2.0kg)を加える。混合した後、粉末は他の機能性賦形剤を添加され、中粘度ポリビニルピロリドンを水に溶解することにより得られた結合剤溶液とともに混練する。流動床において乾燥させ、好適なスクリーンを通して粉砕した後、ヒドロキシプロピルメチルセルロース(35.0kg)および好適な分量の他の賦形剤、たとえば潤滑剤としてのステアリン酸マグネシウムを加え、混合物を、均質な粉末分散体が得られるまでブレンドする。
− pH1で2時間後 耐性(<5%)
− pH6.4で1時間後 耐性(<5%)
− pH7.2で2時間後 9%
− pH7.2で4時間後 28%
− pH7.2で8時間後 86%
ブデソニドMMX(登録商標)組成物
50gのジエチレングリコールモノエチルエーテルを、500gの微結晶性セルロースに均質に分布させ、次いで100gのブデソニドを加え、混合して完全に均質化する。この混合体は、400gのブデソニドをさらに添加され、次いで100gのカルナウバワックスおよび100gのステアリン酸を含有する、60℃の温度で予熱したブレンダー中で分散させる。5分間混練した後、混合物を室温に冷却し、押し出して1mm未満のサイズの顆粒とする。好適なミキサーに、上記のように調製したマトリックス顆粒を投入し、以下の量の親水性賦形剤:1500gのヒドロキシプロピルメチルセルロースおよび500gのPolicarbophil(商標)を加える。構成成分は、マトリックスが均質に分散するまで混合され、次いで2450gの微結晶性セルロース、400gのラクトース、100gのコロイド状シリカ、および50gのステアリン酸マグネシウムを添加される。さらに5分混合した後、混合体を錠剤化して250mg/錠の単位重量とする。
− pH1で2時間後 耐性(<5%)
− pH6.4で1時間後 耐性(<5%)
− pH7.2で2時間後 11%
− pH7.2で4時間後 32%
− pH7.2で8時間後 76%
潰瘍性大腸炎(UC)を有する患者における寛解の維持のためのブデソニドMMX(登録商標)
1日1回投与された実施例2Aと同様の組成を有するブデソニドMMX(ブデソニドMMX)9mg錠は、8週間の療法の後、軽度から中等度のUCを有する患者において、良好な忍容性を示し、臨床的と内視鏡的の両方の寛解の導入および症状解消に有効であることが示された。ブデソニドMMXによる寛解の維持に対する長期療法の潜在的な有効性および安全性を評価するために、第III相の12か月のプラセボ(プラセボ)を対照とした安全性および延長使用試験(extended use study)を行った。
最大12か月にわたる実施例2Bと同様の組成を有するブデソニドMMX 6mg錠の臨床的寛解(すなわち、UCDAIスコアに基づき直腸出血(RB)=0かつ排便回数(SF)=0)の維持に対する有効性を評価するために、2つの第3相試験またはオープンラベル試験の後に臨床的および内視鏡的寛解状態であった122人の患者を、ブデソニドMMX 6mg QDまたはプラセボに無作為化した(1:1)。探索的有効性評価には、1、3、6、9、12か月、および/または試験の終了/早期中止来院の後における、臨床的寛解(主要評価項目)状態にある患者の部分が含まれた。副次的評価項目は、臨床的再発までの時間(RBの再発生および/または患者にとっての正常よりも1〜2回の便/日以上のSFの再発生までの日単位の時間)であった。
安全性解析には、実施例2Aと同様の組成を有するブデソニドMMX 9mg錠に関する2つの第3相試験またはオープンラベル試験の後に臨床的および内視鏡的寛解状態であった123人の患者が含まれた。少なくとも1回用量の実施例2Bと同様の組成を有するブデソニドMMX 6mg錠またはプラセボを与えられたすべての患者が、安全性解析に含まれた。患者を、ブデソニドMMX 6mg QDまたはプラセボに無作為化した(1:1)。全患者安全性判定を、ベースライン、1、3、6、9、12か月の治療、および/または試験の終了/早期中止来院時に行った。
全身性コルチコステロイド(SCS)は、活動性UCにおける短期的な寛解の導入に有効であるが、長期使用は、たとえば骨塩密度(BMD)の低減などの許容できない副作用につながる可能性がある。ブデソニドは、非全身性コルチコステロイド(NSCS)であり、1日1回投与された実施例2Aと同様の組成を有するブデソニドMMX(ブデソニドMMX)9mg錠は、8週間の療法の後、軽度から中等度のUCを有する患者において、良好な忍容性を示すことが示された。この延長使用試験では、実施例2Bと同様の組成を有するブデソニドMMX 6mg錠による12か月にわたる長期療法の後に、BMDを評価した。
全身性コルチコステロイド(SCS)は、活動性潰瘍性大腸炎(UC)における短期的な寛解の導入に有効であるが、長期の使用は、副腎機能の抑制につながり、循環するコルチゾールの低減が生じる可能性がある。有意な長期の副腎抑制は、急性疾病、外傷、手術、または他のストレスの間に副腎クリーゼを引き起こす可能性がある。この12か月試験では、実施例2Bと同様の組成を有するブデソニドMMX 6mg錠による延長療法(extenced therapy)の間に、コルチゾールレベルおよび副腎皮質刺激ホルモン刺激テストを評価した。
潰瘍性大腸炎(UC)を有する患者における追加療法のためのブデソニドMMX(登録商標)
現行の経口療法に追加したときのブデソニドMMXの付加的利益を確立するために、実施例2aと同様の組成を有するブデソニドMMX 9mg錠の無作為化二重盲検プラセボ対照第3b相臨床試験(clinical study)を、軽度または中等度の活動性潰瘍性大腸炎(UC)を有する患者であって、バックグラウンドの経口5−ASA療法で十分に制御されない患者で行う。
活動性の軽度から中等度の潰瘍性大腸炎を有する患者におけるブデソニドMMX(登録商標)(9mg)錠による寛解の導入:多施設、オープンラベルの有効性および安全性試験
活動性の軽度から中等度のUCを有する患者であって、事前の第3相の8週間の導入試験(induction study)において臨床的および内視鏡的寛解を達成することができなかった患者において、実施例2Aと同様の組成を有する経口ブデソニドMMX 9mg徐放錠による8週間のオープンラベル治療の安全性および有効性を判定するために、任意の治療群(ブデソニドMMX 9mg、ブデソニドMMX 6mg、Asacol(登録商標)[メサラミン]2400mg、またはプラセボ)における8週間の導入療法を完了した事前の第3相試験(親試験(Parent Study))からの患者であって、寛解状態でなかった患者を、オープンラベルのブデソニドMMX 9mgによる8週間の治療を受ける本試験への登録に適格とした。よって、事前の第3相試験において事前のブデソニドMMX療法(9mgまたは6mg)を受けた患者は、追加の8週間のブデソニドMMX 9mgを受けることになり、16週間の合計継続期間の治療となる。
活動性の軽度から中等度の潰瘍性大腸炎を有する患者におけるブデソニドMMX(登録商標)(9mg)錠による寛解の導入
2つの同様に設計された無作為化二重盲検プラセボ対照試験を、潰瘍性大腸炎疾患活動性指標(UCDAIが≧4かつ≦10)として定義された活動性の軽度から中等度の潰瘍性大腸炎(UC)を有する合計970人の成人患者で行った。これらの患者のうち899人が、活動性UCと合致する組織構造を有しており、これを主要解析集団とみなした。UCDAIは、排便回数、直腸出血、粘膜外観、および医師による疾患活動性の評定(項目の各々について0から3のスコア)の臨床的判定を包含する4項目のスケール(0から12の合計スコア)である。
Claims (5)
- 5−アミノサリチル酸(5−ASA)を予め投与され、4以上のUCDAIスコアを有する、潰瘍性大腸炎を有する患者を治療するための医薬であって、前記医薬が、同時に、個別にまたは逐次的に使用するための第1の組成物および第2の組成物を組み合わせて含み、
前記第1の組成物は、5−アミノサリチル酸を含み、
前記第2の組成物は、
(1)(a)9mgのブデソニド
(b)少なくとも1種の親油性賦形剤
(c)少なくとも1種の両親媒性賦形剤、および
(d)少なくとも1種の親水性賦形剤
を含む錠剤コアと、
(2)胃耐性フィルムを含む前記錠剤コア上のコーティングと
を含む単一錠剤の形態であることを特徴とする医薬。 - 前記第2の組成物は、最大8週間投与されることを特徴とする請求項1に記載の医薬。
- 前記治療の後に、前記患者の前記UCDAIスコアが1以下であることを特徴とする請求項1または2に記載の医薬。
- 前記患者は、前記第2の組成物が前記患者に投与される前に、潰瘍性大腸炎再燃を経験していることを特徴とする請求項1〜3のいずれか1項に記載の医薬。
- 前記第1の組成物および第2の組成物が、前記患者に同時に投与されることを特徴とする請求項1〜4のいずれか1項に記載の医薬。
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US201261598308P | 2012-02-13 | 2012-02-13 | |
US61/598,308 | 2012-02-13 |
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JP2014557019A Division JP2015506999A (ja) | 2012-02-13 | 2013-02-13 | 少なくとも1つの炎症性要素を呈する腸管疾患を治療するための方法 |
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JP2017210476A JP2017210476A (ja) | 2017-11-30 |
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JP2014557019A Pending JP2015506999A (ja) | 2012-02-13 | 2013-02-13 | 少なくとも1つの炎症性要素を呈する腸管疾患を治療するための方法 |
JP2017138019A Expired - Fee Related JP6472063B2 (ja) | 2012-02-13 | 2017-07-14 | 少なくとも1つの炎症性要素を呈する腸管疾患を治療するための方法 |
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CN (2) | CN110693890A (ja) |
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PT (1) | PT2814495T (ja) |
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FR2974864B1 (fr) * | 2011-05-04 | 2016-05-27 | Snecma | Rotor de turbomachine avec moyen de retenue axiale des aubes |
AU2014262139A1 (en) * | 2013-05-01 | 2015-11-26 | 3 Electric Sheep Pty Ltd | Event notification systems and methods |
WO2015071812A1 (en) * | 2013-11-18 | 2015-05-21 | Wockhardt Limited | Solid oral modified-release composition comprising budesonide or salt thereof |
US10327034B2 (en) * | 2014-03-27 | 2019-06-18 | Tvu Networks Corporation | Methods, apparatus and systems for exchange of video content |
BR112020009171A2 (pt) * | 2017-11-10 | 2020-11-03 | Cosmo Technologies Ltd. | composições orais de rifamicina sv |
CN110585164A (zh) * | 2019-10-08 | 2019-12-20 | 苏州弘森药业股份有限公司 | 一种艾司奥美拉唑镁碳酸氢钠胶囊的制作方法 |
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CA2274943A1 (en) * | 1998-06-17 | 1999-12-17 | Stephen L. Wolman | Compositions for the treatment and prevention of inflammatory diseases of the gastrointestinal tract and methods and uses thereof |
DE19849737A1 (de) * | 1998-10-28 | 2000-05-04 | Falk Pharma Gmbh | Kombinationsmittel zur Behandlung entzündlicher Darmerkrankungen |
US8895064B2 (en) * | 1999-06-14 | 2014-11-25 | Cosmo Technologies Limited | Controlled release and taste masking oral pharmaceutical composition |
PT1183014E (pt) | 1999-06-14 | 2003-12-31 | Cosmo Spa | Composicoes farmaceuticas orais de libertacao controlada e de dissimulacao de sabor |
EP1607087A1 (en) * | 2003-03-27 | 2005-12-21 | Hisamitsu Pharmaceutical Co., Inc. | Medicinal oral preparations for colon delivery, medicinal oral preparations for treating colon cancer and medicinal oral preparations for treating colitis |
CA2662428A1 (en) * | 2006-09-13 | 2008-03-20 | The Procter & Gamble Company | Methods of treatment for ulcerative colitis |
EP2392321A1 (en) * | 2007-06-13 | 2011-12-07 | Jay Pravda | Combined composition for rectal administration for the treatment of inflammatory bowel disease |
EP2298321A1 (en) * | 2009-08-26 | 2011-03-23 | Nordic Pharma | Novel pharmaceutical compositions for treating IBD |
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IN2014DN06662A (ja) | 2015-05-22 |
HK1204927A1 (en) | 2015-12-11 |
BR112014020095A2 (ja) | 2017-06-20 |
DK2814495T3 (da) | 2021-08-23 |
EP2814495B1 (en) | 2021-07-07 |
ES2882880T3 (es) | 2021-12-03 |
CA2864065A1 (en) | 2013-08-22 |
US20200163888A1 (en) | 2020-05-28 |
EP2814495A1 (en) | 2014-12-24 |
AU2013220464A1 (en) | 2014-09-04 |
US20140187517A1 (en) | 2014-07-03 |
US20130225537A1 (en) | 2013-08-29 |
CN104220076A (zh) | 2014-12-17 |
US20150017239A1 (en) | 2015-01-15 |
WO2013120881A1 (en) | 2013-08-22 |
IL234054A0 (en) | 2014-09-30 |
JP2015506999A (ja) | 2015-03-05 |
RU2649807C2 (ru) | 2018-04-04 |
JP2017210476A (ja) | 2017-11-30 |
RU2014137128A (ru) | 2016-04-10 |
PT2814495T (pt) | 2021-08-19 |
BR112014020095A8 (pt) | 2017-07-11 |
US20130209559A1 (en) | 2013-08-15 |
CN110693890A (zh) | 2020-01-17 |
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