JP2021522170A - プレグネノロンの鼻腔内送達のための組成物および方法 - Google Patents
プレグネノロンの鼻腔内送達のための組成物および方法 Download PDFInfo
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Abstract
【選択図】図1
Description
本出願は、その内容全体が参照により本明細書に組み入れられる、2018年4月17日に出願された米国仮特許出願第62/658,946号に対する優先権を主張する。
本明細書で使用される技術的および科学的用語は、別途定義されない限り、本発明が属する技術分野の当業者によって一般的に理解される意味を有する。以下の説明および実施例において参照される材料、試薬などは、特記しない限り、商業的供給源から入手可能である。
プレグネノロン(PREG)は、内因性神経ステロイドの機能を模倣してアセチルコリン放出を誘発するために使用することができる。PREGは、中枢神経系と末梢神経系の両方で、アストロサイトおよびニューロンで発現するチトクロームP450コレステロール側鎖切断酵素(CYP450scc)によってコレステロールから合成される。PREGは、DHEA、テストステロン、プロゲステロン、エストロゲン、およびコルチゾールなどのさまざまな神経活性ステロイドに変換することができる。Melcangi,R.C.et al.,“Role of neuroactive steroids in the peripheral nervous system,”Front.Endocrinol.,2,104(2011)を参照されたい。PREGは、スルホトランスフェラーゼによって自然に硫酸プレグネノロン(PREG−S)に変換される場合もある。Robel,P.et al.,“Biosynthesis and assay of neurosteroids in rats and mice: functional correlates,”J.Steroid Biochem.Mol.Biol.,53,355−360(1995);Dufort,I. et al., “Isolation and characterization of a stereospecific 3beta−hydroxysteriod sulfotransferase(pregnenolone sulfotransferase)cDNA,”DNA Cell Biol.,15,481−487(1996);Kohjitani,A.et al.,“Regulation of SULT2B1a(pregnenolone sulfotransferase)expression in rat C6 glioma cells:relevance of AMPA receptor−mediated NO signaling,”Neurosci.Lett.,430,75−80(2008)を参照されたい。
Ipsilaterally Increasing Acetylcholine Activity
上記のように、本明細書に記載されるのは、それを必要とする対象の脳組織におけるアセチルコリン活性を同側で増加させるための組成物および方法である。脳の一方の半球でアセチルコリン活性を選択的に増加させる能力はこれまで記載されておらず、脳卒中、統合失調症、鬱病、パーキンソン病、およびアルツハイマー病の状況で起こり得るように、脳の特定の領域、例えば脳の特定の半球などでアセチルコリン活性の増加が所望される場合に、明白な利点を提供する。
本明細書に記載の方法によれば、プレグネノロンは、プレグネノロンと、鼻腔内投与のための医薬的に許容される担体とを含む組成物など、鼻腔内投与に適した任意の組成物中で鼻腔内投与することができる。
本明細書に記載されるのは、例えば、脳内の一方の半球でのみアセチルコリン活性を増加させるために、それを必要とする対象の脳組織におけるアセチルコリン活性を同側で増加させるための治療方法、およびそのような方法で使用するためのプレグネノロン製剤である。
また、それを必要とする対象の脳組織におけるアセチルコリン活性を同側で増加させるのに使用される、またはそれを必要とする対象における統合失調症、パーキンソン病、アルツハイマー病、レビー小体型認知症、無関心、自閉症、不安、ストレス、関節リウマチ、外傷性脳損傷、脳卒中、脳卒中後神経保護、双極性障害、鬱病、注意欠陥多動障害、および睡眠障害から選択される疾患もしくは状態を治療するのに使用されるプレグネノロン製剤も提供される。いくつかの実施形態において、対象は、非げっ歯類対象である。プレグネノロン製剤は、医薬的に許容される担体中に有効量のプレグネノロンを含み、医薬組成物としての使用に適し、かつ鼻腔内投与に適合した、本明細書に記載の任意のプレグネノロン製剤を含む任意のプレグネノロン製剤であり得る。いくつかの実施形態において、プレグネノロン製剤は、対象の一方の鼻孔のみへの鼻腔内投与に適合している。
対象。手術時に生後3〜4ヶ月で、体重が400〜500グラムの成体雄ウィスターラット合計10匹を、地元の動物施設(Tierversuchsanlage,University of Dusseldorf、Germany)から入手した。それらをケージ(マクロロンケージ、IV型、60.0×20.0×38.0センチメートル)当たり4匹に群分けし、手術後に個別のケースに分けた。逆明暗サイクル(午前7時(AM)から午後7時(PM)まで消灯)下で収容し、餌と水は自由摂取させた。室温は摂氏20±2度であり、環境の湿度を制御した。2週間の順応後、以下に記載するように動物にマイクロダイアリシスを行った。全ての実験は、動物福祉に関する欧州共同体理事会指令(86/609/EEC)に従って行われ、ドイツの動物保護法当局であるLANUVNordrhein−Westfalenによって承認された。
図1に示すように、対象内の反復測定分散分析について双方向ANOVAのペアワイズ比較を実施して、同側半球へのプレグネノロン(11.2ミリグラム/ミリリットル(mg/mL))および対側半球へのビヒクルの片側鼻腔内投与が各動物の扁桃体における細胞外アセチルコリン(Ach)の放出に与える影響を評価した。扁桃体の分析のために調査した動物の数は次の通りである:n=10。
対象間および対象内の両方の分散分析を実施して、前頭皮質、海馬、および扁桃体におけるプレグネノロン(PREG)(5.6ミリグラム/ミリリットル(mg/mL)、11.2ミリグラム/ミリリットル(mg/mL))またはビヒクルの鼻腔内投与の影響を評価した。前頭皮質の分析のために調査した動物の数は、ビヒクル群でn=7、PREG 5.6mg/mL用量群でn=5、PREG 11.2mg/mL用量群でn=6であった。海馬の分析のために調査した動物の数は、ビヒクル群でn=6、PREG 5.6mg/mL用量群でn=7、PREG 11.2mg/mL用量群でn=5であった。扁桃体の分析のために調査した動物の数(動物38および39を除く)は、ビヒクル群でn=7、PREG 5.6mg/mL用量群でn=5、PREG 11.2mg/mL用量群でn=4であった。
Claims (33)
- 非げっ歯類対象にプレグネノロン製剤を鼻腔内投与することを含む、それを必要とする前記非げっ歯類対象の脳組織におけるアセチルコリン活性を同側で増加させる方法であって、前記プレグネノロン製剤は、医薬的に許容される担体中に有効量のプレグネノロンを含む経鼻内投与に適合した医薬組成物である、方法。
- 前記プレグネノロン製剤は一方の鼻孔にのみ投与され、前記鼻孔の同側脳半球でアセチルコリン活性が増加する、請求項1に記載の方法。
- アセチルコリン活性は、前記鼻孔の対側脳半球では実質的に増加しない、請求項2に記載の方法。
- 前記対象の扁桃体におけるアセチルコリン活性の増加をもたらす、請求項1に記載の方法。
- 前記対象の海馬におけるアセチルコリン活性の増加をもたらす、請求項1に記載の方法。
- 前記アセチルコリン活性は10分以内に増加する、請求項1〜5のいずれか一項に記載の方法。
- 前記脳組織におけるアセチルコリン活性は、少なくとも60分間持続する、請求項1〜6のいずれか一項に記載の方法。
- 前記脳組織におけるアセチルコリン活性は、少なくとも100分間持続する、請求項1〜7のいずれか一項に記載の方法。
- プレグネノロンの前記有効量は、前記対象の体重1キログラム当たり約0.01mg〜約2.0mgである、請求項1〜8のいずれか一項に記載の方法。
- 前記医薬的に許容される担体は、(a)前記製剤の約60質量%〜約98質量%の量で存在する少なくとも1つの親油性または部分的に親油性の担体と、(b)前記製剤の約1質量%〜約20質量%の量で存在する表面張力低下活性を有する少なくとも1つの化合物と、(c)前記製剤の約0.5質量%〜約10質量%の量で存在する少なくとも1つの粘度調整剤と、を含む、請求項1〜9のいずれか一項に記載の方法。
- 前記プレグネノロンは、多孔性賦形剤の細孔内に位置する前記多孔性賦形剤の表面に搭載される、請求項1〜10のいずれか一項に記載の方法。
- 前記対象は、ヒト、非ヒト霊長類、イヌ、ネコ、ウシ、ヒツジ、ウマ、またはウサギである、請求項1〜11のいずれか一項に記載の方法。
- 前記対象は、脳内のアセチルコリン活性の低下に関連する疾患または状態に罹患している、請求項1〜12のいずれか一項に記載の方法。
- 前記疾患または状態は、統合失調症、パーキンソン病、アルツハイマー病、レビー小体型認知症、無関心、自閉症、不安、ストレス、関節リウマチ、外傷性脳損傷、脳卒中、脳卒中後神経保護、双極性障害、鬱病、注意欠陥多動障害、および睡眠障害から選択される、請求項13に記載の方法。
- 前記方法は、記憶および学習障害などの認知機能を改善するのに有効である、請求項1〜14のいずれか一項に記載の方法。
- 必要とする非げっ歯類対象の脳組織におけるアセチルコリン活性を同側で増加させるのに使用される、または必要とする対象における統合失調症、パーキンソン病、アルツハイマー病、レビー小体型認知症、無関心、自閉症、不安、ストレス、関節リウマチ、外傷性脳損傷、脳卒中、脳卒中後神経保護、双極性障害、鬱病、注意欠陥多動障害、および睡眠障害から選択される疾患もしくは状態を治療するために使用される、プレグネノロン製剤であって、医薬的に許容される担体中に有効量のプレグネノロンを含む経鼻内投与に適合した医薬組成物である、プレグネノロン製剤。
- 前記プレグネノロン製剤は、前記対象の一方の鼻孔のみへの鼻腔内投与に適合している、請求項16に記載の使用のためのプレグネノロン製剤。
- 前記プレグネノロン製剤は一方の鼻孔にのみ投与され、前記鼻孔の同側脳半球でアセチルコリン活性が増加する、請求項16〜17のいずれか一項に記載の使用のためのプレグネノロン製剤。
- アセチルコリン活性は、前記鼻孔の対側脳半球では実質的に増加しない、請求項18のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記使用は、前記対象の扁桃体におけるアセチルコリン活性の増加をもたらす、請求項16〜19のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記使用は、前記対象の海馬におけるアセチルコリン活性の増加をもたらす、請求項16〜20のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記アセチルコリン活性は10分以内に増加する、請求項21のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記脳組織におけるアセチルコリン活性は、少なくとも60分間持続する、請求項21〜22のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記脳組織におけるアセチルコリン活性は、少なくとも100分間持続する、請求項21〜23のいずれか一項に記載の使用のためのプレグネノロン製剤。
- プレグネノロンの前記有効量は、前記対象の体重1キログラム当たり約0.01mg〜約2.0mgである、請求項16〜24のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記医薬的に許容される担体は、(a)前記製剤の約60質量%〜約98質量%の量で存在する少なくとも1つの親油性または部分的に親油性の担体と、(b)前記製剤の約1質量%〜約20質量%の量で存在する表面張力低下活性を有する少なくとも1つの化合物と、(c)前記製剤の約0.5質量%〜約10質量%の量で存在する少なくとも1つの粘度調整剤と、を含む、請求項16〜25のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記プレグネノロンは、多孔性賦形剤の細孔内に位置する多孔性賦形剤の表面に搭載される、請求項16〜26のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記対象は、ヒト、非ヒト霊長類、イヌ、ネコ、ウシ、ヒツジ、ウマ、またはウサギである、請求項16〜27のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記対象は、前記脳内のアセチルコリン活性の低下に関連する疾患または状態に罹患している、請求項16〜28のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 前記疾患または状態は、統合失調症、パーキンソン病、アルツハイマー病、レビー小体型認知症、無関心、自閉症、不安、ストレス、関節リウマチ、外傷性脳損傷、脳卒中、脳卒中後神経保護、双極性障害、鬱病、注意欠陥多動障害、および睡眠障害から選択される、請求項29に記載の使用のためのプレグネノロン製剤。
- 前記使用は、記憶および学習障害などの認知機能を改善するのに有効である、請求項16〜30のいずれか一項に記載の使用のためのプレグネノロン製剤。
- 必要とする非げっ歯類対象の脳組織におけるアセチルコリン活性を増加させるための、または必要とする対象における統合失調症、パーキンソン病、アルツハイマー病、レビー小体型認知症、無関心、自閉症、不安、ストレス、関節リウマチ、外傷性脳損傷、脳卒中、脳卒中後神経保護、双極性障害、鬱病、注意欠陥多動障害、および睡眠障害から選択される疾患もしくは状態を治療するための、薬物の調製におけるプレグネノロンの使用であって、前記薬物は、医薬的に許容される担体中に有効量のプレグネノロンを含む経鼻内投与に適合した医薬組成物である、使用。
- 前記薬物は、前記対象の一方の鼻孔のみへの鼻腔内投与に適合している、請求項18に記載の使用。
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CA3198930A1 (en) * | 2020-11-19 | 2022-05-27 | Acousia Therapeutics Gmbh | Non-aqueous gel composition |
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DE60303854T2 (de) | 2003-11-11 | 2006-08-10 | Mattern, Udo | Nasenformulierung mit kontrollierter Freisetzung von Sexualhormonen |
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US9757388B2 (en) * | 2011-05-13 | 2017-09-12 | Acerus Pharmaceuticals Srl | Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels |
JOP20200195A1 (ar) * | 2014-09-08 | 2017-06-16 | Sage Therapeutics Inc | سترويدات وتركيبات نشطة عصبياً، واستخداماتها |
EP3193836A1 (en) * | 2014-09-15 | 2017-07-26 | PharmaSol GmbH | Active-loaded particulate materials for topical administration |
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CN112512505A (zh) | 2021-03-16 |
WO2019202504A1 (en) | 2019-10-24 |
EP3781129A1 (en) | 2021-02-24 |
US20220062165A1 (en) | 2022-03-03 |
KR20210013047A (ko) | 2021-02-03 |
AU2019256828A1 (en) | 2020-12-03 |
CA3097090A1 (en) | 2019-10-24 |
MX2020011025A (es) | 2021-01-29 |
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