したがって、図３Ｃに示すように、ＰＥＲＧ １１．２ｍｇ／ｍＬは、扁桃体におけるアセチルコリン放出の増加を誘発した。
本発明のまた別の態様は、以下のとおりであってもよい。
〔１〕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。
〔２〕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、前記〔１〕に記載の方法。
〔３〕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、前記〔２〕に記載の方法。
〔４〕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、前記〔１〕に記載の方法。
〔５〕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、前記〔１〕に記載の方法。
〔６〕前記アセチルコリン活性は１０分以内に増加する、前記〔１〕～〔５〕のいずれか一項に記載の方法。
〔７〕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、前記〔１〕～〔６〕のいずれか一項に記載の方法。
〔８〕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、前記〔１〕～〔７〕のいずれか一項に記載の方法。
〔９〕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、前記〔１〕～〔８〕のいずれか一項に記載の方法。
〔１０〕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、前記〔１〕～〔９〕のいずれか一項に記載の方法。
〔１１〕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、前記〔１〕～〔１０〕のいずれか一項に記載の方法。
〔１２〕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、前記〔１〕～〔１１〕のいずれか一項に記載の方法。
〔１３〕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、前記〔１〕～〔１２〕のいずれか一項に記載の方法。
〔１４〕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、前記〔１３〕に記載の方法。
〔１５〕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、前記〔１〕～〔１４〕のいずれか一項に記載の方法。
〔１６〕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。
〔１７〕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、前記〔１６〕に記載の使用のためのプレグネノロン製剤。
〔１８〕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、前記〔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。
〔１９〕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、前記〔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。
〔２０〕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、前記〔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。
〔２１〕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、前記〔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。
〔２２〕前記アセチルコリン活性は１０分以内に増加する、前記〔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。
〔２３〕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、前記〔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。
〔２４〕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、前記〔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。
〔２５〕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、前記〔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。
〔２６〕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、前記〔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。
〔２７〕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、前記〔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。
〔２８〕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、前記〔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。
〔２９〕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、前記〔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。
〔３０〕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、前記〔２９〕に記載の使用のためのプレグネノロン製剤。
〔３１〕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、前記〔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。
〔３２〕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。
〔３３〕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、前記〔１８〕に記載の使用。
Therefore, as shown in FIG. 3C, PERG 11.2 mg / mL induced an increase in acetylcholine release in the amygdala.
Another aspect of the present invention may be as follows.
[1] A method for ipsilaterally increasing acetylcholine activity in the brain tissue of the non-rod tooth subject, which comprises intranasal administration of a pregnenolone preparation to the non-rod tooth subject, the pregnenolone. A method, wherein the pharmaceutical product is a pharmaceutical composition suitable for intranasal administration, which comprises an effective amount of pregnenolone in a pharmaceutically acceptable carrier.
[2] The method according to [1] above, wherein the pregnenolone preparation is administered to only one nostril, and acetylcholine activity is increased in the ipsilateral hemisphere of the nostril.
[3] The method according to [2] above, wherein the acetylcholine activity does not substantially increase in the contralateral hemisphere of the nostril.
[4] The method according to [1] above, which results in an increase in acetylcholine activity in the amygdala of the subject.
[5] The method according to [1] above, which results in an increase in acetylcholine activity in the hippocampus of the subject.
[6] The method according to any one of [1] to [5] above, wherein the acetylcholine activity increases within 10 minutes.
[7] The method according to any one of [1] to [6] above, wherein the acetylcholine activity in the brain tissue lasts for at least 60 minutes.
[8] The method according to any one of [1] to [7] above, wherein the acetylcholine activity in the brain tissue lasts for at least 100 minutes.
[9] The method according to any one of [1] to [8] above, wherein the effective amount of pregnenolone is about 0.01 mg to about 2.0 mg per kilogram of the body weight of the subject.
[10] The pharmaceutically acceptable carrier is (a) at least one lipophilic or partially lipophilic carrier present in an amount of about 60% to about 98% by weight of the formulation and (b). ) At least one compound having a surface tension reducing activity present in an amount of about 1% by mass to about 20% by mass of the above-mentioned preparation, and (c) in an amount of about 0.5% by mass to about 10% by mass of the above-mentioned preparation. The method according to any one of the above [1] to [9], which comprises at least one viscosity modifier present.
[11] The method according to any one of [1] to [10] above, wherein the pregnenolone is mounted on the surface of the porous excipient located in the pores of the porous excipient.
[12] The method according to any one of the above [1] to [11], wherein the subject is a human, a non-human primate, a dog, a cat, a cow, a sheep, a horse, or a rabbit.
[13] The method according to any one of the above [1] to [12], wherein the subject suffers from a disease or condition related to a decrease in acetylcholine activity in the brain.
[14] The disease or condition includes schizophrenia, Parkinson's disease, Alzheimer's disease, Levy body dementia, indifference, autism, anxiety, stress, rheumatoid arthritis, traumatic brain injury, stroke, post-stroke neuroprotection, 13. The method according to [13] above, which is selected from bipolar disorder, depression, attention deficit hyperactivity disorder, and sleep disorder.
[15] The method according to any one of [1] to [14] above, wherein the method is effective for improving cognitive functions such as memory and learning disabilities.
[16] Synthetic dysfunction, Parkinson's disease, Alzheimer's disease, Lewy body dementia in subjects used or required to increase acetylcholine activity in brain tissue of non-rodent subjects in need on the same side. , Indifference, autism, anxiety, stress, rheumatoid arthritis, traumatic brain injury, stroke, post-stroke neuroprotection, bipolar disorder, depression, attention deficit hyperactivity disorder, and sleep disorders. A pregnenolone preparation, which is a pharmaceutical composition suitable for intranasal administration, which comprises an effective amount of pregnenolone in a pharmaceutically acceptable carrier.
[17] The pregnenolone preparation for use according to the above [16], wherein the pregnenolone preparation is suitable for intranasal administration to only one nostril of the subject.
[18] The pregnenolone preparation for use according to any one of [16] to [17] above, wherein the pregnenolone preparation is administered to only one nostril and the acetylcholine activity is increased in the ipsilateral hemisphere of the nostril. pharmaceutical formulation.
[19] The pregnenolone preparation for use according to any one of [18] above, wherein the acetylcholine activity is substantially not increased in the contralateral hemisphere of the nostril.
[20] The pregnenolone preparation for use according to any one of [16] to [19], wherein the use results in an increase in acetylcholine activity in the amygdala of the subject.
[21] The pregnenolone preparation for use according to any one of [16] to [20] above, wherein the use results in an increase in acetylcholine activity in the hippocampus of the subject.
[22] The pregnenolone preparation for use according to any one of the above [21], wherein the acetylcholine activity is increased within 10 minutes.
[23] The pregnenolone preparation for use according to any one of [21] to [22] above, wherein the acetylcholine activity in the brain tissue lasts for at least 60 minutes.
[24] The pregnenolone preparation for use according to any one of [21] to [23] above, wherein the acetylcholine activity in the brain tissue lasts for at least 100 minutes.
[25] The effective amount of pregnenolone is about 0.01 mg to about 2.0 mg per kilogram of body weight of the subject, and the pregnenolone for use according to any one of the above [16] to [24]. pharmaceutical formulation.
[26] The pharmaceutically acceptable carrier is (a) at least one lipophilic or partially lipophilic carrier present in an amount of about 60% by weight to about 98% by weight of the formulation, and (b). ) At least one compound having a surface tension reducing activity present in an amount of about 1% by mass to about 20% by mass of the above-mentioned preparation, and (c) in an amount of about 0.5% by mass to about 10% by mass of the above-mentioned preparation. The pregnenolone preparation for use according to any one of [16] to [25] above, which comprises at least one viscosity modifier present.
[27] The pregnenolone is mounted on the surface of the porous excipient located in the pores of the porous excipient for the use according to any one of the above [16] to [26]. Pregnenolone preparation.
[28] The subject is a human, a non-human primate, a dog, a cat, a cow, a sheep, a horse, or a rabbit, and the pregnenolone for use according to any one of the above [16] to [27]. pharmaceutical formulation.
[29] The pregnenolone preparation for use according to any one of [16] to [28] above, wherein the subject suffers from a disease or condition associated with a decrease in acetylcholine activity in the brain.
[30] The disease or condition includes schizophrenia, Parkinson's disease, Alzheimer's disease, Levy body dementia, indifference, autism, anxiety, stress, rheumatoid arthritis, traumatic brain injury, stroke, post-stroke neuroprotection, The pregnenolone formulation for use according to [29] above, which is selected from bipolar disorder, depression, attention deficit hyperactivity disorder, and sleep disorder.
[31] The pregnenolone preparation for use according to any one of the above [16] to [30], wherein the use is effective for improving cognitive function such as memory and learning disabilities.
[32] schizophrenia, Parkinson's disease, Alzheimer's disease, Lewy body dementia, indifference, autism in the subject to increase acetylcholine activity in the brain tissue of the required non-rodent subject or in the subject in need , Anxiety, stress, rheumatoid arthritis, traumatic brain injury, stroke, post-stroke neuroprotection, bipolar disorder, depression, attention deficit hyperactivity disorder, and drugs for treating diseases or conditions selected from sleep disorders Use of Pregnenolone in preparation, wherein the drug is a pharmaceutical composition suitable for intranasal administration comprising an effective amount of Pregnenolone in a pharmaceutically acceptable carrier.
[33] The use according to [18] above, wherein the drug is suitable for intranasal administration to only one nostril of the subject.