JP6579956B2 - 神経変性疾患および他の疾患の治療のための併用治療薬および方法 - Google Patents
神経変性疾患および他の疾患の治療のための併用治療薬および方法 Download PDFInfo
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Description
本出願は、2012年11月28日に出願された米国仮特許出願第61/730,761号の利益を請求するものであり、その全ての内容が参照により本明細書に組み込まれる。
本発明は、国立衛生研究所(National Institutes of Health)助成金番号1R44AG034760−01A1を含む連邦政府の支援を受けて成された。
図2は、SH−SY5Y神経芽細胞腫細胞において、10−9Mブリオスタチン−1と同様に、2μMレチノイン酸によってもsAPP形成が増加する(p<0.01)ことを示す。10−9Mおよび10−10Mのブリオスタチン−1とともに2μM濃度のレチノイン酸(RA)を加えた時に相加効果が観察された。
油性ブリオスタチン溶液は、保存剤としてのビタミンE、ならびに生物学的利用率を高めるためのレシチンおよび中鎖脂肪酸トリグリセリド乳化剤を含むオリーブ油に溶解した所望の量のブリオスタチンを用いて作製される。溶解したブリオスタチンを含む油は、窒素パージおよびヘッドによりゲルカプセルに封入される。代替として、溶解したブリオスタチンを含む油は、液体剤形として投与される。代替として、溶解したブリオスタチンを含む油はまた、乳化されて液体製剤として投与されてもよい。乳化は、油性経口製剤に伴うあまり望ましくない味および舌触りをいくらか遮蔽することができる。
油性ブリオスタチンおよびレチノイン酸の溶液は、保存剤としてのビタミンE、ならびに生物学的利用率を高めるためのレシチンおよび中鎖脂肪酸トリグリセリド乳化剤を含むオリーブ油に溶解した所望の量のブリオスタチンおよびレチノイン酸を用いて作製される。ブリオスタチンおよびレチノイン酸を含む油は、窒素パージおよびヘッドによりゲルカプセルに封入される。代替として、溶解したブリオスタチンおよびレチノイン酸を含む油は、液体剤形として投与される。さらなる代替として、溶解したブリオスタチンおよびレチノイン酸を含む油はまた、乳化されて液体製剤として投与されてもよい。乳化は、油性経口製剤に伴うあまり望ましくない味および舌触りをいくらか遮蔽することができる。
前述の方法に従って、ポリマーおよびブリオスタチン1を含む微粒子を調製した。その結果を下の表1に要約する。
前述の方法に従って、ポリマーと1つ以上のブリオスタチンおよびレチノイド化合物とを含む微粒子を調製する。
早期発症型アルツハイマー病と関連するスウェーデン変異型アミロイド前駆体タンパク質(sweAPP)およびPS1(プレセニリン−1)遺伝子を担持するマウス系統B6C3−Tgを、5〜6月齢で水迷路試験に供した。これらの試験は、油性製剤中5マイクログラム/マウスの用量でブリオスタチン−1を隔日経口投与されたマウスが、APP/PS1変異によって引き起こされるアルツハイマー病によってもたらされる記憶喪失に対して、対照動物に見られた記憶獲得能力と比較して有意な保護を示したことを示唆するものである。
Claims (18)
- 有効量のブリオイド(Bryoid)および有効量のレチノイドを含む、αセクレターゼによるプロセシングの増強が有益である1つ以上の疾患の治療のための、または、αセクレターゼ活性の上昇に応答性の疾患の治療のための製剤であって、
前記ブリオイド(Bryoid)およびレチノイドが、1〜1000ナノメートルの直径を有しかつバイオポリマーを含む複数の微粒子に保持され、
前記ブリオイド(Bryoid)が、ブリオスタチン1〜20からなる群に、さらに第1のブリオイド(Bryoid)、第2のブリオイド(Bryoid)および第3のブリオイド(Bryoid)を含む群から選択され、ここで、前記第1のブリオイド(Bryoid)は、測定モノアイソトピック質量として874.2Amuを有するブリオイドB10であり、前記第2のブリオイド(Bryoid)は、測定モノアイソトピック質量として888.9Amuを有するブリオイドB12であり、および、前記第3のブリオイド(Bryoid)は、測定モノアイソトピック質量として846.6Amuを有するブリオイドB14Bであり、ならびに
前記バイオポリマーが、ポリ(D,L−ラクチド−コグリコシド)である、
前記製剤。 - 前記レチノイドが、レチノイン酸、レチノール、酢酸レチノール、パルミチン酸レチノール、13−シス−レチノイン酸およびベキサロテンからなる群から選択される、請求項1に記載の製剤。
- 前記レチノイドが、αセクレターゼの発現を増加させる量で存在する、請求項1または2に記載の製剤。
- 前記ブリオイド(Bryoid)が、αセクレターゼの産生を刺激する量で存在する、請求項1から3のいずれか1項に記載の製剤。
- 前記ブリオイド(Bryoid)が、1週間当たり1平方メートルの表面積当たり0.1〜50マイクログラムの投与量で存在する、請求項1から4のいずれか1項に記載の製剤。
- 前記ブリオイド(Bryoid)が、1週間当たり1平方メートルの表面積当たり5〜10マイクログラムの投与量で存在する、請求項5に記載の製剤。
- 前記レチノイドが、1日当たり1.0〜240mgの投与量で存在する、請求項1から6のいずれか1項に記載の製剤。
- 前記レチノイドが、レチノイン酸である、請求項1から7のいずれか1項に記載の製剤。
- 前記バイオポリマーが、耐酸性である、請求項1から8のいずれか1項に記載の製剤。
- 前記ポリ(D,L−ラクチド−コグリコシド)が、25〜75%がラクチドであり、残りがグリコシドである、ラクチドとグリコシドの比率を有する、請求項1から9のいずれか1項に記載の製剤。
- 前記微粒子が、水溶液中で再構成するために凍結乾燥される、請求項1から10のいずれか1項に記載の製剤。
- 前記微粒子が、経口投与のために懸濁液中に保持される、請求項1から10のいずれか1項に記載の製剤。
- 前記微粒子が、錠剤、カプセル剤、ゲルキャップ、および散剤からなる群から選択される経口剤形中に保持される、請求項1から10のいずれか1項に記載の製剤。
- αセクレターゼによるプロセシングの増強が有益である1つ以上の疾患、または、αセクレターゼ活性の上昇に応答性の疾患が、神経変性疾患、癌、ウイルス潜伏感染、および眼性疾患からなる群から選択される、請求項1から13のいずれか1項に記載の製剤。
- 前記神経変性疾患が、アルツハイマー病、ハッチンソン病、パーキンソン病、クールー病、クロイツフェルト・ヤコブ病、ダウン症候群、および海綿状脳症からなる群から選択される、請求項14に記載の製剤。
- 前記癌が、前立腺癌、黒色腫、リンパ腫、腎臓癌、および食道癌からなる群から選択される、請求項14に記載の製剤。
- 前記ウイルス潜伏感染が、HIVまたはヘルペスに関連する疾患である、請求項14に記載の製剤。
- 前記有効量のブリオイド(Bryoid)が、1日当たり体重1キログラム当たり3〜10ugの投与量で存在する、請求項1から17のいずれか1項に記載の製剤。
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US20120309818A1 (en) | 2007-12-31 | 2012-12-06 | Jonathan Steven Alexander | Chronic inflammation and transplantation |
WO2009129361A2 (en) | 2008-04-16 | 2009-10-22 | University Of Utah Research Foundation | Macrocyclic compounds and methods of making and using thereof |
KR20190026056A (ko) | 2008-04-21 | 2019-03-12 | 오토노미, 인코포레이티드 | 귀 질환 및 병태를 치료하기 위한 귀 조제물 |
WO2010014990A2 (en) * | 2008-08-01 | 2010-02-04 | The Board Of Trustees Of The University Of Illinois | Method of promoting neurogenesis by modulating secretase activities |
US20100166806A1 (en) * | 2008-12-29 | 2010-07-01 | Aphios Corporation | Combination therapy comprising the use of protein kinase C modulators and Histone Deacetylase inhibitors for treating HIV-1 latency |
WO2010144499A2 (en) * | 2009-06-09 | 2010-12-16 | Medolution Limited | Urea derivatives as kinase inhibitors |
EP2776018B1 (en) * | 2011-11-13 | 2021-08-25 | Cognitive Research Enterprises, Inc. | Pkc activators and combinations thereof |
US9034347B2 (en) | 2011-12-19 | 2015-05-19 | Arphios Corporation | Drug delivery system and method for the treatment of neuro-degenerative disease |
US20150291616A1 (en) | 2012-11-27 | 2015-10-15 | Aphios Corporation | Bryoid compositions, methods of making and use thereof |
US10828276B2 (en) | 2012-11-28 | 2020-11-10 | Aphios Corporation | Combination therapeutics and methods for the treatment of neurodegenerative and other diseases |
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WO2014085494A1 (en) | 2014-06-05 |
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HK1218882A1 (zh) | 2017-03-17 |
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