WO2018221729A1 - 脳萎縮予防または治療剤 - Google Patents
脳萎縮予防または治療剤 Download PDFInfo
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- WO2018221729A1 WO2018221729A1 PCT/JP2018/021223 JP2018021223W WO2018221729A1 WO 2018221729 A1 WO2018221729 A1 WO 2018221729A1 JP 2018021223 W JP2018021223 W JP 2018021223W WO 2018221729 A1 WO2018221729 A1 WO 2018221729A1
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- Prior art keywords
- brain atrophy
- agent
- alzheimer
- compound
- brain
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Definitions
- the present invention relates to a preventive or therapeutic agent for brain atrophy comprising 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or a salt thereof as an active ingredient.
- Dementia is a neurodegenerative disease in which cognitive function is remarkably reduced due to brain atrophy or cerebrovascular disorder.
- AD Alzheimer's dementia
- the pathogenesis of AD is complex, but amyloid ⁇ protein (A ⁇ ) aggregates to form senile plaques, or phosphorylated tau protein (p-Tau) aggregates to lead to neurofibrillary tangles Is considered to be the cause (Non-Patent Document 2).
- the number of AD patients is estimated to be about 1.16 million or more in Japan.
- Non-patent Document 5 Non-patent Document 5
- the therapeutic agents for AD currently used in Japan include four drugs of the acetylcholinesterase inhibitor donepezil hydrochloride, galantamine hydrobromide, rivastigmine and the N-methyl-D-aspartate receptor antagonist memantine hydrochloride. Both are present and can reduce core or peripheral symptoms.
- these drugs are symptomatic treatments that improve core symptoms or peripheral symptoms for a certain period, and are not drugs that suppress neurodegeneration of AD. Even if these drugs show a temporary cognitive improvement effect at the beginning of use, the cognitive function is generally worse than the cognitive function before treatment after 48 weeks or more (Non-patent Document 6).
- Compound A 3- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol (hereinafter referred to as “Compound A”) or a salt thereof has a neuroprotective action and promotes nerve regeneration. It is known to be a compound having an action and neurite extension action and useful as a therapeutic agent for diseases of central and peripheral nerves (Patent Document 1). In addition, it is described that in the case of oral administration, 0.01 to 500 mg per day may be divided into 1 to several doses per day for oral administration (Patent Document 2).
- An object of the present invention is to provide a drug for suppressing the progression of AD and a method for suppressing the progression of AD.
- a preventive or therapeutic agent for brain atrophy containing Compound A or a salt thereof as an active ingredient containing Compound A or a salt thereof as an active ingredient.
- the agent for preventing or treating brain atrophy according to (1) wherein 100 mg to 400 mg of Compound A per dose is orally administered once a day.
- the agent for preventing or treating brain atrophy according to (1) wherein 160 mg or 320 mg of Compound A per dose is orally administered once a day.
- AD probable AD, suspicious (possible) AD, preclinical AD, prodromal Alzheimer type dementia, mild cognitive impairment due to Alzheimer type dementia
- MCI mild cognitive impairment
- the present invention also provides the following inventions.
- B Compound A or a salt thereof for use in the prevention or treatment of brain atrophy.
- C A method of preventing or treating brain atrophy by administering Compound A or a salt thereof to a patient.
- D Use of compound A or a salt thereof for the production of a preventive or therapeutic agent for brain atrophy.
- E A brain atrophy inhibitor comprising compound A or a salt thereof as an active ingredient.
- F Compound A or a salt thereof for use in suppressing brain atrophy.
- G A method of suppressing brain atrophy by administering Compound A or a salt thereof to a patient.
- H Use of compound A or a salt thereof for the production of a brain atrophy inhibitor.
- Administration of compound A or a salt thereof can prevent or treat brain atrophy observed in neurodegenerative diseases such as aging or AD, progressive supranuclear palsy, and frontotemporal dementia.
- a numerical range indicated using “to” means a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
- Compound A means 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol.
- Examples of the salt of the compound A include a conventionally known salt in a basic group such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group.
- Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
- alkali metals such as sodium and potassium
- alkaline earth metals such as calcium and magnesium
- ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
- preferable salts include pharmacologically acceptable salts, and more preferable salts include salts with maleic acid.
- the present invention includes all such isomers, and also includes hydrates, It includes solvates and all crystal forms.
- Prevention means preventing the onset of a particular disease or one or more symptoms resulting from the disease.
- treating is meant reducing or ameliorating one or more symptoms resulting from the disease, as well as delaying the progression of the disease, for the particular disease the subject is afflicted with.
- prevention means preventing or delaying the occurrence or progression of brain atrophy.
- treatment is meant preventing or delaying the progression of brain atrophy.
- Mild to moderate AD is the National Institute of Neurology and Stroke / Alzheimer's Disease and Related Disorders Association (National Institute of Neurological and Communicative Disorders and Stroke / the Aldheimer's Dissease and Relative Diagnosis) ) Alzheimer's disease can be clinically diagnosed.
- a “mild to moderate” diagnosis can be adequately made by a regular physician using standard criteria.
- clinical diagnosis of mild to moderate, moderate and moderate to severe AD is made with reference to the standardized Mini-MentalStateExamination (MMSE; score of 0 to 30 points).
- MMSE Felstein, Folstein and McHugh, 1975
- MMSE is a simple cognitive function test by a questioning method for patients.
- MMSE is not the only method for clinical diagnosis of AD grade but is convenient.
- Apolipoprotein E is a kind of apolipoprotein that constitutes lipoprotein and is involved in lipoprotein recognition and lipid metabolism. There are three isoforms of ApoE, ApoE2, ApoE3 and ApoE4. ApoE4 genotype encoding ApoE4 and the amount of amyloid ⁇ protein deposited in the brain are correlated, and ApoE4 genotype is a risk gene for Alzheimer's disease It has been reported that.
- neurodegenerative diseases include AD, Probable AD, Possible AD, Preclinal AD, Prodromic AD, MCI due to AD, MCI, progressive supranuclear palsy, and frontotemporal dementia.
- AD, Probable AD, Possible AD, Preclinic AD, Prodral AD, MCI due to AD and MCI are mentioned, More preferably, AD, MCI due to AD and MCI are mentioned, More preferably AD and MCI due to AD.
- the diagnosis of Probable AD, Possible AD, Preclinical AD, Prodromal AD and MCI due to AD is described in Alzheimers Dement, May 2011, Vol. 7, No.
- Brain atrophy in AD results from the loss of neurons and synapses that begin in the entorhinal cortex. The lesion then spreads throughout the marginal area of the temporal lobe, including hippocampal formation, and neuronal loss and atrophy become observed throughout the neocortex-related areas of the temporal lobe, parietal lobe, and frontal lobe.
- Volumetric MRI vMRI allows in vivo assessment of brain structure volume and provides a measure of the rate of atrophy. The results of vMRI studies suggest that brain atrophy patterns that reflect the pathological progression of AD can be reliably detected and followed over time (Atiya et al. 2003).
- Hippocampal volume derived from vMRI is associated with histological hippocampal volume, neuronal loss and degree of AD (Jack et al. 2002), and changes in olfactory cortex thickness are associated with AD-related nerves. It is considered to be an early and sensitive indicator of degeneration (Knight et al. 2009; Holland et al. 2009). Longitudinal vMRI measurements of local and total brain volume changes complement cognitive assessment in that they are not affected by temporary symptom improvement and provide an early indicator of the ability of drugs to affect AD atrophy .
- Compound A or a salt thereof used in the present invention can be produced by a method known per se or a combination thereof, or a method described in Patent Document 1.
- Compound A or a salt thereof used in the present invention includes excipients, binders, disintegrants, disintegration inhibitors, caking / adhesion inhibitors, lubricants, absorption / adsorption carriers, solvents, extenders, isotonic agents.
- Agent solubilizer, emulsifier, suspending agent, thickener, coating agent, absorption accelerator, gelation / coagulation accelerator, light stabilizer, preservative, moisture-proofing agent, emulsification / suspension / dispersion stability
- Various pharmaceutical additives such as agent, coloring agent, deoxygenation / antioxidant, flavoring / flavoring agent, coloring agent, foaming agent, antifoaming agent, soothing agent, antistatic agent, buffer / pH adjuster Formulated orally (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, solutions, syrups, etc.), injections, eye drops, nasal or transdermal It can be set as a pharmaceutical formulation such as.
- a tablet is preferable.
- the drug is formulated by a usual method.
- the administration method of Compound A is not particularly limited, but is appropriately determined according to the form of the preparation, the patient's age, sex and other conditions, and the degree of symptoms of the patient.
- the dose of Compound A is appropriately selected according to the usage, patient age, sex, disease form, other conditions, and the like. In general, for adults, 40 to 500 mg of compound A may be administered in 1 to several divided doses, more preferably 100 to 400 mg of compound A in 1 to several divided doses per day. More preferably, 160 mg or 320 mg per day as Compound A may be administered once.
- administration of Compound A or a salt thereof can further include prevention or treatment by administration of an acetylcholinesterase inhibitor (AChEI).
- AChEI include donepezil hydrochloride, galantamine hydrochloride, rivastigmine tartrate, and tacrine hydrochloride.
- the subject may have received a pre-treatment or treatment with administration of AChEI for at least 6 months prior to administration of Compound A or a salt thereof.
- Test Example 1 Phase 2 multicenter randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Compound A in patients with mild to moderate AD (selection criteria): From 42 days prior to study drug assignment to assignment In addition, patients were screened based on the following selection criteria. ⁇ Patients with probable AD who are 55 to 85 years old when obtaining consent for screening ⁇ Patients with MMSE score of 12-22 at screening ⁇ Patients with Modified Hachinski IschemiaScale score of 4 or less ⁇ Before baseline Patients who have been treated with donepezil hydrochloride or rivastigmine transdermal system at a stable dose for at least 4 months and for 3 months before baseline.
- the compound A-administered group tended to decrease in volume less than the placebo-administered group.
- the difference in the effect on the hippocampal volume change between the compound A low dose group and the placebo group was statistically significant.
- Test Example 2 Preclinical Phase II Multicenter Randomized Double-Blind Placebo Control Study for Evaluating Efficacy and Safety of Compound A in Patients with Mild to Moderate AD The following selection criteria from 28 days before study drug assignment to assignment Based on the above, patients were screened. The matched patients (373) were randomly divided into the following two groups and the study was started. Target (selection criteria): ⁇ Patients with probable AD between 50 and 90 years of age when obtaining consent for screening ⁇ Patients with an MMSE score of 15 to 24 at screening ⁇ Patients with Modified Hachinski IschemiaScale score of 4 or less ⁇ Before baseline Patients who were treated with donepezil hydrochloride at a stable dose for at least 6 months and 3 months prior to baseline.
- Composition of patient groups with brain MRI or CT at screening matched AD (1) Active drug administration group: 224 mg of test compound (160 mg as Compound A) orally once daily for 52 weeks (176 patients) (2) Placebo administration group: Placebo was orally administered once a day for 52 weeks (178 patients) Evaluation methods: Volumetric MRI The brain volume of the subjects was measured by vMRI scan after screening and 52 weeks to quantify the whole brain and hippocampal volume changes for each subject, and the brain atrophy was evaluated from the changes from the screening. Statistical analysis: The mean change, the standard deviation, and the difference from the placebo-administered group of the whole brain and hippocampal volume after 52 weeks were calculated. Results: Shown below.
- the compound A-administered group tended to decrease in volume less than the placebo-administered group.
- Per tablet with coating agent (Opadry 03F44057, 00F440000 (hypromellose 2910: 71.5%, macrogol 6000: 14.166%, talc: 7.167%, titanium oxide: 7.067%, iron sesquioxide: 0.1%), Nippon Colorcon) After coating at a rate of 8 mg, a small amount of carnauba wax was added to obtain film-coated tablets.
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Abstract
Description
認知症の症状には、認知機能障害を中心とした中核症状および認知機能障害を持つ患者が周囲とかかわる際に示す問題行動のような周辺症状がある(非特許文献5)。現在国内で用いられているADの治療薬は、アセチルコリンエステラーゼ阻害剤のドネペジル塩酸塩、ガランタミン臭化水素酸塩、リバスチグミンおよびN-methyl-D-aspartate受容体拮抗薬のメマンチン塩酸塩の4剤が存在し、いずれも中核症状または周辺症状を低減することができる。しかし、これらの薬剤は中核症状または周辺症状を一定期間改善する対症療法であり、ADの神経変性を抑制する薬剤ではない。これらの薬剤は使用当初に一時的な認知機能改善効果を示しても、概して48週以上経過すると認知機能は治療前の認知機能より悪化する(非特許文献6)。
(1)化合物Aまたはその塩を有効成分として含有する脳萎縮予防または治療剤。
(2)1回あたり化合物Aとして100mg~400mgを1日1回経口投与される、(1)に記載の脳萎縮予防または治療剤。
(3)1回あたり化合物Aとして160mgまたは320mgを1日1回経口投与される、(1)に記載の脳萎縮予防または治療剤。
(4)神経変性疾患を伴う患者に投与されるための、(1)~(3)のいずれか1に記載の脳萎縮予防または治療剤。
(5)AD、ほぼ確実な(Probable)AD、疑いがある(Possible)AD、臨床前段階にある(Preclinical)AD、前駆期(Prodromal)アルツハイマー型認知症、アルツハイマー型認知症による軽度認知障害(MCI due to AD)または軽度認知障害(MCI)を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
(6)AD、MCI due to ADまたはMCIを伴う患者に投与されるための、(1)~(3)のいずれか1に記載の脳萎縮予防または治療剤。
(7)ADを伴う患者に投与されるための、(1)~(3)のいずれか1に記載の脳萎縮予防または治療剤。
(8)MCI due to ADを伴う患者に投与されるための、(1)~(3)のいずれか1に記載の脳萎縮予防または治療剤。
(a)脳萎縮を予防または治療するための、化合物Aまたはその塩を有効成分として含有する医薬組成物。
(b)脳萎縮の予防または治療において使用するための、化合物Aまたはその塩。
(c)化合物Aまたはその塩を患者に投与して脳萎縮を予防または治療する方法。
(d)脳萎縮予防または治療剤の製造のための、化合物Aまたはその塩の使用。
(e)化合物Aまたはその塩を有効成分として含有する脳萎縮抑制剤。
(f)脳萎縮の抑制において使用するための、化合物Aまたはその塩。
(g)化合物Aまたはその塩を患者に投与して脳萎縮を抑制する方法。
(h)脳萎縮抑制剤の製造のための、化合物Aまたはその塩の使用。
本明細書において、特に断らない限り、各用語は、次の意味を有する。
塩基性基における塩としては、たとえば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
治療とは、対象が罹患している特定の疾患に対してその疾患から生じる1以上の症状を軽減または改善すること、ならびにその疾患の進行を遅延させることを意味する。
本発明の実施形態においては、たとえば、神経変性疾患などの疾患を伴う患者において、予防とは、脳萎縮の発生または進行を阻止もしくは遅延させることを意味する。治療とは、脳萎縮の進行を阻止または遅延させることを意味する。
「軽度~中等度」の診断は、標準的な基準を用いて通常の医師が十分になしうる。たとえば、標準化されたMini-MentalStateExamination(MMSE;0~30点のスコア)の数値を参考に、軽度~中等度、中等度および中等度~重度ADを臨床診断する。MMSE(Folstein, Folstein and McHugh,1975)は、患者への質問法による簡便な認知機能検査である。見当識、記憶、計算・注意力、言語機能などについて評価する。合計スコアは30点であり、得点が低いほど、認知機能の障害の程度が高度である。
本発明における試験例においては、試験開始(スクリーニング)時点でのMMSEスコアが12~22の患者を軽度~中等度ADと定義した。なお、MMSEがADの等級を臨床診断するための唯一の方法ではなく便宜的なものであることに留意すべきである。
ADにおける脳の萎縮は、嗅内皮質で始まるニューロンおよびシナプスの喪失から生じる。その後、病変は、海馬形成を含む側頭葉の辺縁領域全体に広がり、ニューロンの喪失および萎縮が側頭葉、頭頂葉および前頭葉の新皮質関連領域全体で観察されるようになる。
Volumetric MRI(vMRI)は、脳構造体積のin vivo評価を可能にし、萎縮速度の尺度を提供する。vMRI研究の結果は、ADの病理学的進行を反映する脳の萎縮のパターンが時間の経過とともに確実に検出され、追跡され得ることを示唆している(Atiya et al.2003)。海馬および嗅内皮質を含む内側頭葉の萎縮は、ADのvMRI研究で長い間報告されている(Jack et al.1997)。vMRIに由来する海馬の体積は、組織学的海馬の体積、ニューロンの喪失およびADの程度と関連しており(Jack et al.2002)、嗅内皮質の厚さの変化はADに関連する神経変性の早期かつ感受性の指標であると考えられている(Knight et al.2009;Holland et al.2009)。局所および全脳容積変化の縦方向のvMRI測定は、一時的な症状の改善の影響を受けないという点で認知評価を補完し、ADによる萎縮に影響を及ぼす薬剤の能力の早期指標を提供する。
上記薬剤は、通常の方法により製剤化される。
化合物Aの投与量は、用法、患者の年齢、性別、疾患の形態、その他の条件などに応じて適宜選択される。
通常、成人に対して、化合物Aとして1日40~500mgを1回から数回に分割して投与すればよく、より好ましくは、化合物Aとして1日100~400mgを1回から数回に分割して投与すればよく、さらに好ましくは、化合物Aとして1日160mgまたは320mgを1回投与すればよい。
本発明において、対象は化合物Aまたはその塩の投与前に少なくとも6ヵ月間、AChEIの投与による予備または治療を受けていてもよい。
試験化合物として、化合物Aのマレイン酸塩を用いた。
対象(選択基準):治験薬割付の42日前から割付までに、下記の選択基準に基づいて患者のスクリーニングを行った。
・スクリーニングの同意取得時に55歳以上85歳以下で、ほぼ確実な(probable)ADの患者
・スクリーニング時のMMSEスコアが12~22の患者
・Modified Hachinski IschemiaScaleスコアが4以下の患者
・ベースライン前に少なくとも4ヵ月間およびベースライン前に3ヶ月間安定した投与量でドネペジル塩酸塩またはリバスチグミン経皮システムで治療を受けた患者
・ドネペジル塩酸塩またはリバスチグミン経皮システムに加えてメマンチンも投与されている患者に関しては、ベースライン前に少なくとも4ヵ月間およびベースライン前に3ヶ月間安定した投与量でメマンチンの治療を受けた患者
・スクリーニング時の脳MRIまたはCTがADに合致する患者
群の構成:上記適合した患者(484名)を下記の3群に無作為に分け、試験を開始した。
(1)高用量投与群:224mgの試験化合物(化合物Aとして160mg)を1日1回4週間経口投与後、448mgの試験化合物(化合物Aとして320mg)を1日1回48週間経口投与(158名)
(2)低用量投与群:224mgの試験化合物(化合物Aとして160mg)を1日1回52週間経口投与(166名)
(3)プラセボ投与群:プラセボを1日1回52週間経口投与(158名)
評価方法:
Volumetric MRI
スクリーニングおよび52週後にvMRIスキャンによって対象の脳体積を測定し、対象ごとの全脳(脳全体)および海馬の体積変化を定量化し、スクリーニングからの変化から脳の萎縮を評価した。
また、対象ごとの全脳および101区域(ブロードマンの脳地図(1~52)のうち、左脳および右脳に各々存在する区域を分けて101の区域に分割)の体積変化を定量化し、スクリーニングからの変化から脳の萎縮を評価した。
統計解析:
52週後の全脳および海馬体積のベースラインからの変化をMixed-effect Modelにより、高用量投与群とプラセボ群、および低用量投与群とプラセボ投与で群間比較した。モデルには、投与群を固定効果、年齢、各脳体積(脳全体または海馬)のベースライン、MMSEのベースラインおよびApoE4遺伝子型(陽性/陰性)を共変量として、治験実施施設を変量効果として含めた。
また、52週後の全脳および101区域の各体積のベースラインからの変化を、高用量投与群とプラセボ群、および低用量投与群とプラセボ投与で群間比較した。
結果:以下に示す。
また、化合物Aの高用量投与群でも、低用量投与群と同様の傾向が認められた。
治験薬割付28日前から割付までに下記の選択基準に基づいて患者のスクリーニングを行った。適合した患者(373名)を下記の2群に無作為に分け、試験を開始した。
対象(選択基準):
・スクリーニングの同意取得時に50歳以上90歳以下で、ほぼ確実な(probable)ADの患者
・スクリーニング時のMMSEスコアが15~24の患者
・Modified Hachinski IschemiaScaleスコアが4以下の患者
・ベースライン前に少なくとも6ヵ月間およびベースライン前に3ヶ月間安定した投与量でドネペジル塩酸塩で治療を受けた患者
・スクリーニング時の脳MRIまたはCTがADに合致する患者
群の構成:
(1)実薬投与群:224mgの試験化合物(化合物Aとして160mg)を1日1回52週間経口投与(176名)
(2)プラセボ投与群:プラセボを1日1回52週間経口投与(178名)
評価方法:
Volumetric MRI
スクリーニングおよび52週後にvMRIスキャンによって対象の脳体積を測定し、対象ごとの全脳および海馬の体積変化を定量化し、スクリーニングからの変化から脳の萎縮を評価した。
統計解析:
52週後の全脳および海馬体積のベースラインからの変化量の平均、標準偏差およびプラセボ投与群との差を算出した。
結果:以下に示す。
化合物Aのマレイン酸塩174.03gにステアリン酸マグネシウム(ステアリン酸マグネシウム,メルク)0.9726gを加え、30分間混合した。この混合末を乾式造粒機(TF-LABO(ロール加圧3MPa),フロイント産業)にて圧縮成形し、成形された固形物を整粒した。得られた整粒末60.0gに乳糖(フローラック90,メグレ・ジャパン)49.51g、結晶セルロース(セオラスPH302,旭化成ケミカルズ)16.50gおよびクロスカルメロースナトリウム(プリメロース,DMVジャパン)6.67gをそれぞれ目開き850μmの篩で篩過して加え、10分間混合した。この混合末にステアリン酸マグネシウム0.6667gを加え、30分間混合した。この混合末を錠剤径8.5mmのダブルアール面の杵を用いて打錠圧約12kNで打錠機(HT-P18A,畑鐵工所)にて打錠し、1錠250mgの円形の素錠を得た。フィルムコーティング機:DRC-200(パウレック)にて素錠にコーティング剤を1錠あたり8mgの割合でコーティングした後、微量のカルナウバロウ(ポリシングワックス-105,日本ワックス)を添加し、フィルムコーティング錠を得た。
化合物Aのマレイン酸塩53.70 gにマンニトール(パーテックM200,メルク)60.90 gおよびクロスカルメロースナトリウム3.60 gを加え、10分間混合した。この混合末にステアリン酸マグネシウム1.80 gを加え、30分間混合した。この混合末を錠剤径8.5mmのダブルアール面の杵を用いて打錠圧約10 kNで打錠し、1錠250mgの円形の素錠を得た。素錠にコーティング剤(オパドライ03F44057、00F440000(ヒプロメロース2910:71.5%,マクロゴール6000:14.166%,タルク:7.167%,酸化チタン:7.067%,三二酸化鉄:0.1%),日本カラコン)を1錠あたり8mgの割合でコーティングした後、微量のカルナウバロウを添加し、フィルムコーティング錠を得た。
化合物Aのマレイン酸塩1988.89gにステアリン酸マグネシウム11.11gを加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末107.13gに、マンニトール26.21g、エチルセルロース(エトセル100FPプレミアム,ダウケミカル)7.50g、結晶セルロース(セオラスKG-1000,旭化成ケミカルズ)3.75g、クロスポビドン(コリドンCL-SF,BASF)3.75gおよびクロスカルメロースナトリウム0.75gを加え、30分間混合した。この混合末にステアリン酸マグネシウム0.90gを加え、5分間混合した。この混合末を錠剤径8.5mmのダブルアール面の杵を用いて打錠圧約7kNで打錠し、1錠315mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり9mgの割合でコーティングした後、微量のカルナウバロウを添加して、フィルムコーティング錠を得た。
Claims (8)
- 1-(3-(2-(1-ベンゾチオフェン-5-イル)エトキシ)プロピル)アゼチジン-3-オールまたはその塩を有効成分として含有する脳萎縮予防または治療剤。
- 1回あたり1-(3-(2-(1-ベンゾチオフェン-5-イル)エトキシ)プロピル)アゼチジン-3-オールとして100mg~400mgを1日1回経口投与される、請求項1に記載の脳萎縮予防または治療剤。
- 1回あたり1-(3-(2-(1-ベンゾチオフェン-5-イル)エトキシ)プロピル)アゼチジン-3-オールとして160mgまたは320mgを1日1回経口投与される、請求項1に記載の脳萎縮予防または治療剤。
- 神経変性疾患を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
- アルツハイマー型認知症、ほぼ確実な(Probable)アルツハイマー型認知症、疑いがある(Possible)アルツハイマー型認知症、臨床前段階にある(Preclinical)アルツハイマー型認知症、前駆期(Prodromal)アルツハイマー型認知症、アルツハイマー型認知症による軽度認知障害(MCI due to AD)または軽度認知障害を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
- アルツハイマー型認知症、アルツハイマー型認知症による軽度認知障害(MCI due to AD)または軽度認知障害を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
- アルツハイマー型認知症を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
- アルツハイマー型認知症による軽度認知障害(MCI due to AD)を伴う患者に投与されるための、請求項1~3のいずれか1項に記載の脳萎縮予防または治療剤。
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JPWO2018221728A1 (ja) | 2017-06-02 | 2020-04-02 | 富士フイルム富山化学株式会社 | アルツハイマー型認知症予防または治療剤 |
MX2019014310A (es) * | 2017-06-02 | 2022-06-10 | Fujifilm Toyama Chemical Co Ltd | Agente para prevenir o tratar atrofia cerebral. |
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KR20190137936A (ko) | 2019-12-11 |
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SG11201911512SA (en) | 2020-01-30 |
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ZA201907973B (en) | 2022-03-30 |
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CA3067453C (en) | 2021-11-23 |
RU2019138166A (ru) | 2021-07-09 |
EP3632431A1 (en) | 2020-04-08 |
RU2019138166A3 (ja) | 2021-07-09 |
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