JP2016501225A - 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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Abstract
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 (49)
- 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に、有効量のBryoidおよび有効量のレチノイドを含む、剤形。
- 前記Bryoidは、ブリオスタチン1〜20からなる群から選択され、第1のBryoid、第2のBryoid、および第3のBryoidを含む、請求項1に記載の製造物品。
- 前記レチノイドは、レチノイン酸である、請求項3に記載の製造物品。
- 前記レチノイドは、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4に記載の製造物品。
- 前記Bryoidは、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に記載の製造物品。
- 前記Bryoidは、1週間当たり1平方メートルの表面積当たり0.1〜50マイクログラムの用量の投与のために存在する、請求項1に記載の製造物品。
- 前記Bryoidは、1週間当たり1平方メートルの表面積当たり5〜10マイクログラムの用量の投与のために存在する、請求項7に記載の製造物品。
- 前記レチノイドは、1日当たり1.0〜240mgの用量で存在する、請求項3に記載の製造物品。
- 前記レチノイドは、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経口レチノイドの群から選択される、請求項9に記載の製造物品。
- αセクレターゼ活性の上昇の原因となる疾患の治療のための、バイオポリマーが複数の球を含み、前記球が1〜1000ナノメートルの直径を有する、製造物品としての前記バイオポリマー中の有効量のBryoidおよびレチノイド。
- 前記バイオポリマーは、耐酸性である、請求項10に記載の製造物品。
- 前記バイオポリマーは、ポリ(D,L−ラクチド−コグリコシド)である、請求項11に記載の製造物品。
- 前記ポリ(D,L−ラクチド−コグリコシド)は、25〜75%がラクチドであるラクチドとグリコシドの比率を有する、請求項12に記載の製造物品。
- 前記微粒子は、水溶液中で再構成するために凍結乾燥される、請求項10に記載の製造物品。
- 前記微粒子は、経口投与のために懸濁液中に保持される、請求項10に記載の製造物品。
- 前記微粒子は、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10に記載の製造物品。
- 複数の微粒子中に保持された有効量のBryoidおよびレチノイドを投与するステップを含み、前記微粒子は、バイオポリマーを含み、1〜1000ナノメートルの直径を有する、神経変性疾患を治療する方法。
- 前記Bryoidは、ブリオスタチン1〜20からなる群から選択され、第1のBryoid、第2のBryoid、および第3のBryoidを含む、請求項17に記載の方法。
- 前記レチノイドは、レチノイン酸である、請求項17に記載の方法。
- 前記レチノイドは、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19に記載の方法。
- 前記Bryoidは、αセクレターゼの産生を刺激する量で存在する、請求項17に記載の方法。
- 前記Bryoidは、1週間当たり1平方メートルの表面積当たり0.1〜50マイクログラムの用量で投与される、請求項17に記載の方法。
- 前記Bryoidは、1週間当たり1平方メートルの表面積当たり5〜10マイクログラムの用量で投与される、請求項22に記載の方法。
- 前記レチノイドは、1日当たり1.0〜240mgの用量で投与される、請求項20に記載の方法。
- 前記レチノイドは、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経口レチノイドの群から選択される、請求項20に記載の方法の物品。
- 前記バイオポリマーは、耐酸性である、請求項17に記載の方法。
- 前記バイオポリマーは、ポリ(D,L−ラクチド−コグリコシド)である、請求項27に記載の方法。
- 前記ポリ(D,L−ラクチド−コグリコシド)は、25〜75%がラクチドであるラクチドとグリコシドの比率を有する、請求項28に記載の方法。
- 前記微粒子は、水溶液中で再構成するために凍結乾燥される、請求項17に記載の方法。
- 前記微粒子は、経口投与のために懸濁液中に保持される、請求項17に記載の方法。
- 前記微粒子は、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17に記載の方法。
- 製造物品として、神経変性疾患、癌、ウイルス潜伏感染、および眼性疾患を治療するための経口投与のために経口的に許容される油性媒体に溶解された有効量のBryoidおよびレチノイド。
- 前記神経変性疾患は、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33に記載の製造物品。
- 前記癌は、前立腺癌、黒色腫、リンパ腫、および腎臓癌、食道および他の癌である、請求項33に記載の製造物品。
- 前記ウイルス潜伏感染は、HIVおよびヘルペスに関連する、請求項33に記載の製造物品。
- 前記有効量のBryoidは、1日当たり体重1キログラム当たり約3〜10ugである、請求項33に記載の製造物品。
- 前記有効量のレチノイドは、1日1.0〜240mgの用量で投与される、請求項33に記載の製造物品。
- 経口的に許容される油性媒体に溶解された有効量のBryoidおよびレチノイドを経口投与するステップを含む、神経変性疾患を治療する方法。
- 静脈内投与によって有効量のBryoidおよびレチノイドを経口投与するステップを含む、神経変性疾患を治療する方法。
- 前記有効量のBryoidは、1日当たり体重1キログラム当たり約3〜10ugである、請求項39に記載の方法。
- 前記有効量のレチノイドは、1日1.0〜240mgの用量で投与される、請求項39に記載の方法。
- 経口的に許容される油性媒体に溶解された有効量のBryoidおよびレチノイドを経口投与するステップを含む、癌を治療する方法。
- 静脈内投与によって有効量のBryoidおよびレチノイドを経口投与するステップを含む、癌を治療する方法。
- 前記有効量のBryoidは、1日当たり体重1キログラム当たり約3〜10ugである、請求項43に記載の方法。
- 前記有効量のレチノイドは、1日1.0〜240mgの用量で投与される、請求項43に記載の方法。
- 経口的に許容される油性媒体に溶解された有効量のBryoidおよびレチノイドを経口投与するステップを含む、ウイルス潜伏感染を治療する方法。
- 静脈内投与によって有効量のBryoidおよびレチノイドを経口投与するステップを含む、ウイルス潜伏感染を治療する方法。
- 前記有効量のBryoidは、1日当たり体重1キログラム当たり約3〜10ugである、請求項48に記載の方法。
- 前記有効量のレチノイドは、1日1.0〜240mgの用量で投与される、請求項48に記載の方法。
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US9994585B2 (en) | 2007-12-31 | 2018-06-12 | Aphios Corporation | Transplantation therapies |
US9034347B2 (en) | 2011-12-19 | 2015-05-19 | Arphios Corporation | Drug delivery system and method for the treatment of neuro-degenerative disease |
WO2014085494A1 (en) | 2012-11-28 | 2014-06-05 | Aphios Corporation | Combination therapeutics and methods for the treatment of neurodegenerative and other diseases |
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US20150297555A1 (en) | 2015-10-22 |
US10828276B2 (en) | 2020-11-10 |
WO2014085494A8 (en) | 2015-04-23 |
CN105228614A (zh) | 2016-01-06 |
HK1218882A1 (zh) | 2017-03-17 |
EP2925314A1 (en) | 2015-10-07 |
EP2925314A4 (en) | 2016-06-01 |
EP2925314B1 (en) | 2020-04-01 |
WO2014085494A1 (en) | 2014-06-05 |
JP6579956B2 (ja) | 2019-09-25 |
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