JP2010540618A - 幼児の成長および発達を増大するための内在性カンナビノイド - Google Patents
幼児の成長および発達を増大するための内在性カンナビノイド Download PDFInfo
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Abstract
Description
本発明は、内在性カンナビノイド(EC)及びその誘導体を使用して、幼児における、摂食、成長及び発達を促進することに関する。特に、本発明は、増量した水準のECを含む幼児用処方物及びその調製法に関する。
マリファナ(Cannabis sativa)植物中の主要活性分子、Δ9−テトラヒドロカンナビノール(THC)は、CB1及びCB2で表される少なくとも2つの特定の受容体を活性化する。1992年以来、これらの受容体に対する内在性リガンドがいくつか、脳及び末梢神経組織から単離され、「内在性カンナビノイド」(EC;例えば、(非特許文献1を参照)と名付けられている。
本発明は、組成物、特には、増量した量のECを含む幼児用処方物に関する。
「幼児」及び「赤ん坊」という用語は、本明細書では、互いに交換可能な用語として使用し、年齢が約1歳以下の個体を指し、0〜約4カ月齢の幼児、約4〜約8カ月齢の幼児、約8〜約12カ月齢の幼児、出生時において2,500g未満の低出生時体重の幼児、妊娠期間約36週間未満の、典型的には、妊娠期間約26〜約34週間の未熟児、及び少ない体重増加及び/又は成長障害を患っている幼児を含む。
内在性カンナビノイド(EC)は、CB1及びCB2受容体に対する内在性のリガンドであり、ヒト及びその他の動物の体内で天然に生産される。EC、特に2AGは、ヒトの母乳の中に見出された。Frideら、2001年に示されているように、ウシの母乳は、抽出脂質1g当たり、1.0と2.4μgの間のECを含み、ヒトの母乳は、抽出脂質1g当たり、6.4〜8.7μgのECを含む。
本発明の1つの実施形態においては、内在性カンナビノイド促進性化合物が幼児用処方物の不可欠の部分として投与される。
本発明の内在性カンナビノイド又は内在性カンナビノイド促進性化合物は、小腸内での徐放を可能とする腸溶コーティングでカプセル化されてもよい。内在性カンナビノイドは、そのような徐放を必要とする適切な試剤と共にカプセル化されてもよい。内在性カンナビノイド又は内在性カンナビノイド促進性化合物は、それゆえ、腸を通過した後にまで早めに消化されないように、凍結乾燥され、凍結乾燥又は乾燥された処方物と共にパッケージされてもよい。
本発明明細書において、幼児、子供又は青年における摂食、成長又は発達を増大させるための及び/又は幼児における成長障害(FTT)を治療するための、内在性カンナビノイド又は内在性カンナビノイド促進性化合物を含む、新規の医薬組成物を開示する。
環境操作技法を用いて、出生後24時間以内で、マウス(ICR種)のそれぞれのリターの半分を同日に生まれた別のリターの雌親にクロス育成した。2つの両方のリターのマウスの仔を、1匹の雌親が4匹の仔を育てるの(「小リター」)と、他の雌親が18〜20匹の仔を育てるの(大リター)とになるように、2匹の雌親の間に分けた。大リターで育てられた仔は、混雑している環境のために悪い栄養状態を経験すると期待された。それぞれのリターの半分には、内在性カンナビノイド2−アラキドノイルグリセロール(2−AG)又はCannabis sativa (マリファナ)植物中の主要心理活性分子であるTHCを、生後5日間毎日、注射した。使用した投与量は、1若しくは5mg/kg THC又は0.1、1若しくは5mg/kg 2−AGであった。体重を毎日記録した。小及び大のリターからの仔の体重を、二元配置の分散分析により分析した。
妊娠している雌(Sabra種又はICR種)を、妊娠がはっきりした時(妊娠12〜14日)に別に収容した。仔は、出生後24時間以内に、2種のビヒクル(EtOH:emulphor:食塩水=1:18)注射、又は特定のCB1受容体拮抗薬SR141716A(リモナバン)+ビヒクルでの注射を行った。注射は、30ゲージの注射針を用いて皮下(s.c.)で首に(10μl/体重g)行い、2回目の注射は、側腹部に行った。「リター効果」を最小にするために(Fride及びWeinstock、1984年)、種々の処置はそれぞれのリター内の仔に対して投与した。仔は、生後8日の間、毎日検査した。
「乳首吸いつき」:「養い」母親に、ケタミン(100mg/kg)及びキシラジン(20mg/kg)の腹腔内(i.p.)注射により麻酔を掛け、(乳首をくわえていない)を0、(乳首を弱くくわえている)を1、又は(乳首を強くくわえている)を2として記録して、仔の乳首吸いつきの強さについて観察した(Calamandrei及びValanzano、1994年;Wilsonら、1981年に基づく)。
(ICR種)のマウスの新生仔(出生後1日)に、SR141716(SR、20又は40mg/kg)を、前記した(Fride、2004年;Frideら、2003年;Frideら、2001年)ように皮下で(SC)注射した。さらに、同腹の仔に、SRを直接脳へ、2つの深さ(2〜3mm)で及びいくつかの投与量、4.5、9.0又は22.5μg(皮下注射に比べて、50から10倍の間で低濃度である)で注射した。図8A〜Eで判るように、中枢に注射する投与計画のいずれも、仔の成長になんらの効果も示さなかったが、一方、両方の投与量での皮下注射では、それぞれの実験で(図8A〜E)体重の増加が著しく妨げられた。
図9Aは、発達のより進んだ段階で生まれた野生トゲネズミ(acomys cahirinus)に比較して、実験マウス(ICR種)の出生後生後2週間の成長カーブで見て、成熟の相対的状態を示している。ここで見られるように、トゲネズミの出生の日には、体重は、ICRマウスが出生後9日で達するものと等しい。このことは、Clancyとその同僚により設計されたモデル(Clancyら、2007年)により予想される脳の成熟における差、すなわち、トゲネズミの出生の日は、実験マウスの出生後8日に相当するということとよく似ている。
Claims (24)
- 液体処方物1リットル当たり、少なくとも約0.2mgの内在性カンナビノイドを含む幼児用処方物。
- 内在性カンナビノイド促進性化合物をさらに含む、請求項1に記載の幼児用処方物。
- 液体処方物1リットル当たり、少なくとも約0.05mgの内在性カンナビノイド促進性化合物を含む幼児用処方物。
- 幼児、子供又は青年の摂食、成長又は発達を促進するための、内在性カンナビノイド若しくは内在性カンナビノイド促進性化合物、又はこれらの組合せを活性成分として含む、医薬組成物。
- 前記内在性カンナビノイドが、アナンダマイド、2−アラキドノイルグリセロール(2AG)、ノラジンエーテル、N−アラキドノイルグリセロールドーパミン(NADA)及びビローダミンからなる群から選択される、請求項1から3のいずれかに記載の幼児用処方物又は請求項4に記載の医薬組成物。
- 前記内在性カンナビノイド促進性化合物が、分解酵素の阻害薬又は再取り込み阻害薬である、請求項2又は請求項3に記載の幼児用処方物又は請求項4に記載の医薬組成物。
- 前記内在性カンナビノイド促進性化合物が、脂肪酸グリセロールエステルである、請求項2又は請求項3に記載の幼児用処方物又は請求項4に記載の医薬組成物。
- 前記脂肪酸グリセロールエステルが、2−パルミトイルグリセロール又は2−リノレオイルグリセロールである、請求項7に記載の幼児用処方物又は医薬組成物。
- 液体処方物1リットル当たり、少なくとも約0.05mgの内在性カンナビノイド促進性化合物を含む、請求項2に記載の幼児用処方物。
- 粉末である、請求項1から3のいずれかに記載の幼児用処方物。
- 液体である、請求項1から3のいずれかに記載の幼児用処方物。
- 前記内在性カンナビノイドが、末梢に限定されたカンナビノイドベースの化合物である、請求項1又は請求項2に記載の幼児用処方物又は請求項4に記載の医薬組成物。
- 幼児の摂食、成長又は発達を促進するための、請求項1から3のいずれかに記載の幼児用処方物。
- 前記幼児が成長障害(FTT)を患っている、請求項13に記載の幼児用処方物。
- 摂食、成長又は発達の増大を必要とする幼児に、摂食、成長又は発達を促進するのに十分な量で内在性カンナビノイドを含む処方物を投与するステップを含む、幼児の摂食、成長又は発達を増大させるための方法。
- 前記幼児に投与される前記処方物が、該幼児に、少なくとも約0.04mg/kg/日の前記内在性カンナビノイドを提供するのに十分であるか、又は該幼児が、少なくとも0.2mg/日の該内在性カンナビノイドを消費する、請求項15に記載の方法。
- 前記処方物が、内在性カンナビノイド促進性化合物をさらに含む、請求項15又は16のいずれかに記載の方法。
- 前記幼児が成長障害(FTT)を患っている、請求項15から17のいずれかに記載の方法。
- 摂食、成長又は発達の促進を必要とする幼児、子供又は青年に、摂食、成長又は発達を促進するのに十分な量で内在性カンナビノイドを含む医薬組成物を投与するステップを含む、幼児、子供又は青年の摂食、成長又は発達を促進するための方法。
- 前記医薬組成物が、内在性カンナビノイド促進性化合物をさらに含む、請求項19に記載の方法。
- 摂食、成長又は発達の促進を必要とする幼児に、摂食、成長又は発達を促進するのに十分な量で内在性カンナビノイド促進性化合物を含む処方物を投与するステップを含む、幼児の摂食、成長又は発達を促進するための方法。
- 前記処方物が、液体処方物1リットル当たり、少なくとも約0.05mgの内在性カンナビノイド促進性化合物を含む、請求項21に記載の方法。
- 前記幼児が成長障害(FTT)を患っている、請求項21に記載の方法。
- 摂食、成長又は発達の促進を必要とする幼児、子供又は青年に、摂食、成長又は発達を促進するのに十分な量で内在性カンナビノイド促進性化合物を含む医薬組成物を投与するステップを含む、幼児、子供又は青年の摂食、成長又は発達を促進するための方法。
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US96051207P | 2007-10-02 | 2007-10-02 | |
PCT/IL2008/001314 WO2009044402A1 (en) | 2007-10-02 | 2008-10-02 | Endocannabinoids for enhancing growth and development in infants |
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US (1) | US20110172305A1 (ja) |
EP (1) | EP2205240A1 (ja) |
JP (1) | JP2010540618A (ja) |
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US20220071922A1 (en) * | 2018-12-26 | 2022-03-10 | Clear Lake Research, Llc | Delivery of health benefits through component formulation |
CN111202767A (zh) * | 2019-09-04 | 2020-05-29 | 汉义生物科技(北京)有限公司 | 大麻全草提取物在改善tau蛋白和β-淀粉样蛋白病理损伤中应用 |
CN114748429A (zh) | 2020-12-29 | 2022-07-15 | 汉义生物科技(北京)有限公司 | 一种水溶性大麻素制剂及其制备方法 |
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WO2002065997A1 (en) * | 2001-02-21 | 2002-08-29 | Unilever Plc | Antiperspirant or deodorant compositions |
JP2005511632A (ja) * | 2001-11-23 | 2005-04-28 | アストラゼネカ・アクチエボラーグ | 胃食道逆流疾患の治療のための新しい使用 |
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IE52535B1 (en) * | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
CH671155A5 (ja) * | 1986-08-18 | 1989-08-15 | Clinical Technologies Ass | |
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IL132661A (en) * | 1999-10-31 | 2008-11-26 | Raphael Mechoulam | Agonists specific for peripheral cannabinoid receptors |
AU2001266289A1 (en) * | 2000-06-23 | 2002-01-02 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | 2-arachidonylglycerol (2-ag) - an inhibitor of tumor necrosis factor -alfa and neuroprotector of brain in closed head injury |
US6913778B2 (en) * | 2001-12-21 | 2005-07-05 | Wyeth | Infant formula compositions comprising increased amounts of alpha-lactalbumin |
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2008
- 2008-10-02 WO PCT/IL2008/001314 patent/WO2009044402A1/en active Application Filing
- 2008-10-02 US US12/681,273 patent/US20110172305A1/en not_active Abandoned
- 2008-10-02 CN CN2008801188665A patent/CN101998855A/zh active Pending
- 2008-10-02 EP EP08836529A patent/EP2205240A1/en not_active Withdrawn
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WO2002065997A1 (en) * | 2001-02-21 | 2002-08-29 | Unilever Plc | Antiperspirant or deodorant compositions |
JP2005511632A (ja) * | 2001-11-23 | 2005-04-28 | アストラゼネカ・アクチエボラーグ | 胃食道逆流疾患の治療のための新しい使用 |
Non-Patent Citations (3)
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JPN5010014002; Fride E: 'Endocannabinoids in the central nervous system--an overview.' Prostaglandins Leukot Essent Fatty Acids Vol.66 No.2-3, 200202, pp.221-233 * |
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JPN6013022672; Fride E et al.: 'Critical role of the endogenous cannabinoid system in mouse pup suckling and growth.' Eur J Pharmacol. Vol.419 No.2-3, 20010511, pp.207-214 * |
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US20110172305A1 (en) | 2011-07-14 |
WO2009044402A1 (en) | 2009-04-09 |
EP2205240A1 (en) | 2010-07-14 |
CN101998855A (zh) | 2011-03-30 |
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