1324935 七、發明說明： 發明範圍 本發明乃關於治療以非恢復活力性睡眠為特徵之原發性失眠症（依 DSM-IV所規範或ICD-10所規範之非器質性失眠）的方法，關於使用褪黑激 素或其他為此目的所製成藥劑内的某些複合劑，及關於混合多種複合劑組 合而成的藥劑，以改善原發性失眠症患者睡眠的質與量。 發明背景 按，睡眠障礙之存在相當的普遍，其原因又極為複雜，尤其在西方工 業國豕中，估計成人人口中大約三分之一敘述至少偶而會有睡眠障礙，而 這些睡眠障礙人口中，至少有一半抱怨其睡眠障礙已經存在數年β而在美 國專利編號US5,776,969號(James)中，透露有一種以特定組合的化學複合 劑，來治療各種睡眠障礙的方法；失眠，在其中所討論界定的事項中，可 含或不含非恢復活力性睡眠。 原發性失眠症在精神障礙診斷與統計手冊第四版(DSM-IV)(美國精神 醫學會，1994)中的定義為：多數的主要抱怨是難入睡或難維持睡眠，或非 恢復活力性睡眠，已經至少有一個月。此睡眠障礙(或其合併的日間疲憊） 導致具臨床意義的苦惱或損害到其社會，職業，或其他重要的機能。更甚 者’依此定義，單是非恢復活力性睡眠一項，若導致自天機能障礙，即足 以確立診斷為原發性失眠症。 依國際疾病分類第十版（ICD-10)(世界衛生組織，1991)描述非器 質性失眠症為睡眠的量及/或質的不足1^。它並指出"雖然其睡眠量在 主觀及/或客觀判斷下屬正常範圍内，仍有人極受睡眠品質低下之苦。， 4 1324935 據ICD-10的診斷方針敘述說，要確定診斷出原發性失 眠症的必要臨床特徵有以下： a、 抱怨難狀睡，或是難以鋪睡眠，或是睡眠品質低下； b、 睡眠障礙之發生，至少每週有三次，且已有一個月； c、 在夜裡及自天耽心失眠並對其後果過度不安； d、 睡眠不足的量及/或質’或引起顯著的苦權，或干擾社會與職業 機能。如此，ICD~10反覆強調了睡眠的量與睡眠的質在麟失眠症上具同 等的重要。因此，本發明關連到原發性失眠症(DSM_IV)或非器質性失眠症 (ICD-10)。 而因為，天然的激素褪黑激素在正常人血液内之濃度，比起自天來夜 間會增高（依據特定檔案，見如美國專利編號US5 498 423號(Zisapel))， 且因為缺乏夜間褪黑激素與睡眠障礙有關連性，尤其是在但不只限於老年 人’投予外源性褪黑激素以改善睡眠障礙的可行性，已有進行研究，且亦 是很多科學文獻的科目。 因此’例如.在James,S.P.及其同僚之文(Neuropsychopharmacology 1990,3:19-23)，褪黑激素（1毫克與5毫克）及安慰劑，在晚間1〇時45分， 一晚各一種藥’給予1〇位以睡眠多電波先篩選過的失眠症患者，其平 均年齡為33.4歲。這些患者（雖不一定有非恢復活力性睡眠相關的失眠症） 確有可經由PSG驗證出的睡眠量之不足。投予褪黑激素並未改變入睡潛伏 期、睡眠效能、全部睡眠時間或入睡後覺醒。 患者敘述有改善睡眠的品質，雖然他們在早上並沒有得到更多的休 5 1324935 息，且認為他們在使用褪黑激素時全部睡眠時間較為縮短。 而在Ellis,C.M.及其同僚之文獻(J·Sleep Res.，1996,5:61-65)，對 心理生理失眠症患者，在晚間8時投予褪黑激素（5毫克)一週，睡眠量或質 並未報告出有變化；於15位患者中，有8位無法分辨出何時為掩黑激素治 療時期。 另，在Hughes，R.J·及其同僚之文獻（Sleep 1998,21:52-68)，予 睡眠多電波篩選過的不能持續睡失眠症的老年患者，在睡前3〇分投予立即 釋出型與控制釋出型的褪黑激素(0 . 5毫克與5毫克），並在夜間中途投予 立即釋出型褪黑激素製劑0.5毫克。他們發現這兩種褪黑激素製劑都可減 少入睡潛伏期，但並未改變入睡後覺醒時間（此為不能持續睡失眠症之重 要變數）或全部睡眠時間。他們並未發現褪黑激素有改變睡眠品質或白天 的情緒及敏覺。 又，在MacFarlane J.G•及其同僚之文獻(Bi〇i pSyChiatry 1991，30(4):371-6)報告指出，褪黑激素（75毫克口服），連續14天於每日 晚間10時投予13位失眠症患者，其主觀評估，認為有顯著增加全部睡眠時 間及曰間敏覺桂，但其中7/13患者認為對主觀舒適感覺並無顯著作用。 因此，由已發表文獻中，並無證據顯示，投與外源褪黑激素（或其他 掩黑激素類激導劑，褪黑激素作用劑，或褪黑激素拮抗劑），在本發明的 劑量範圍内，對患有非恢復活力性睡眠特徵之原發性失眠症患者，會有可 能改善其睡眠的恢復活力之品質。 然而，相對於上述已發表文獻的結果，本發明意外地發現了，褪黑激 1324935 素（及其他複黑激素類激導劑，褪黑激素作用劑，或褪黑激素拮抗劑）實 際上增進了原發性失眠症患者其睡眠之恢復活力的品質。 本發明所適用的褪黑激素作用劑與褪黑激素拮抗劑，包含(但不只限於) 美國專利編號US 5,151，446號，US 5, 318,994號，US 5,385, 944號，US 5,403,851號，及國際專利97/00069號說明書所述之複合劑。 在此所引述的美國專利與參考文獻均係作為參考之用。 發明摘要 本發明’一方面提供了從褪黑激素，其他棍黑激素類激導劑，褪黑激 素作用劑及褪黑激素拮抗劑，其有效量在〇 〇〇25毫克到5〇毫克之間，當中 選用至少一種複合劑製成藥劑，以治療及改善原發性失眠症患者睡眠的恢 復活力品質；在此種藥劑也是由至少一種製藥學上可接受的稀釋劑，防腐 劑，抗氧化劑，溶解劑，乳化辅佐劑或載體所組成。 另一方面’本發明提供一方法以治療或改善原發性失眠症患者的恢復 活力睡眠品質《此法乃從褪黑激素，其他褪黑激素類激導劑，褪黑激素作 用劑及褪黑激素结抗劑當中，至少選用一種複合劑，投予有效劑量予上述 患者，上述有效劑量乃介於0·0025毫克至5〇毫克之間。 還有-方面’本發明提供一藥劑以改善原發性失眠症患者的睡眠的質 與量。此法乃從；黑齡’其他概齡類激導冑，褪黑激素作用劑及褪 黑激素拮抗劑當巾’至少翻—種複合劑，及另外至少加—種選自抗焦慮 劑，抗抑繫劑，安眠劑，鎮靜劑’降血壓劑，止麵，多巴胺致劑，抗精 神病劑，小鎮靜劑，厭食劑與抗發炎藥物，有效的治療藥物，此外還要加 7 1^24935 上至^種製藥學上可接受的稀釋劑，防腐劑，抗氧化劑，溶解劑，乳化 輔佐劑或載體。 發明詳述 本發明的藥劑’或其用途，最好再依下述特色之至少-種來分別： (I)為適合經由口服，肛門，注射，口腔黏膜，肺内（如：吸入），或 經皮投予； cm為單_量型式；每單位劑量至少由一前述複合劑組成，其劑量 介於0.025毫克到1〇毫克之間； (Π )為延長釋放型配方； (IV) 積儲型式’該積儲型式會在體内，在預選時問内，慢慢釋出前述 至少一種成； (V) 也是加上額外選自抗焦慮劑，多巴胺作用劑，抗精神病藥物，小 鎮靜劑’厭储與抗發《藥龄至彡__種治療藥物所組成。 本發明所提供的藥劑中’至少一種複合物者，其劑量較宜用到能改善 原發性失眠症患者(依前述定義），睡眠的恢復活力品質的劑量；而至少加 一項額外治療藥物者’其劑量較宜用到能增進患者睡眠量的劑量。 本發明中治療及改善原發性失眠症患者(依前述定義）睡眠的恢復活力 品質的方法’即從褪黑激素，其他褪黑激素類激箏劑，褪黑激素作用劑及 褪黑激素拮抗劑當中，至少選用一種複合劑投予有效劑量，此法較宜以藥 劑型式投予；此藥劑型式也是包含至少一種製藥學上可接受的稀釋劑，防 腐劑，抗氧化劑，溶解劑，乳化輔佐劑或載體。 1324935 藥劑宜更進一步依上述（I )、（H)、（III)及(IV)之至少一種特性分類。 與本發明有關的藥劑，製藥學上可接受的稀釋劑，防腐劑，抗氧化劑， 溶解劑，乳化劑，輔佐劑與載體，乃為傳統上用於製藥處方者。 口服投予時，藥劑可以製成例如錠劑，膠囊，乳劑，溶液，糖漿或懸 浮液。注射投予時’藥劑可以製成例如玻璃製安瓿，或懸浮液，水溶基劑 或油溶基劑的溶液或乳劑。用到浮懸劑、安定劑及/或分散劑的，當然要 考慮到其溶解度’或作用複合劑在特定製品基劑内之溶解度。藥劑也可能 另外含有例如符合生理的防腐劑與抗氧化劑。藥劑也可能以傳統的栓劑基 劑，譬如可可脂或其它甘油脂，當成栓劑使用。 如上所述’從褪黑激素，其他褪黑激素類激導劑，複黑激素作用劑及 褪黑激素拮抗劑當中，至少選用一種複合劑，能與促進睡眠量有用途的其 他複合劑結合投與（即同時，分另，或連續結合）。這些其他複合劑包含 例如：選自抗焦慮、抗抑.劑，安眠劑(benzodiazepine類以及 non-benzodiazepine類），鎮靜劑，降血壓劑，止痛藥多巴胺作用劑，抗 精神病劑，小鎮靜劑，厭食劑與抗發炎藥物等的額外至少一種治療藥物。 此些額外治療藥物例如 adinazolam, allobarbital, alonimid, alprazolam, amitriptyl ine, amobarbital, amoxapine, bentazepam, benzoctamine, brot izolam, bupropion, busprione, butabarbital, butalbital, capuride, carb ocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipr amine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, de sipramine, dexclamol, diazepam, dichloral phenazone, divalproex, diphe 9 1324935 nhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flu nitrazepam, flurazepam, fluvoxanine, fluoxetine, fosazepam, glutethim lde, halazepam,hydroxyzine,imipramine, lithium, lorazepam, lormetaze pam, maproti1ine, mecloqualone, mephobarbital, meprobamate, methaqual one, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortript yline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, pe rphenazine, phenelzine, phenobarbital, prazepam, promethazine, propof ol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, ser traline, suproclone, temazepam, thioridazine, tracazolate, tranylcypr omaine, trazodone, triazolam, trepipam, reicetamide,triclofos,triflu operazine, trimetozine, trimipramine, uldazepam, valproate, venlafaxi ne, zaleplon, zolazepam, zolpidem, zopiclone，及其鹽類，及其組合適合 的抗抑鬱劑類包括正腎上腺素回收抑制劑，選擇性血清素回收抑制劑 (SSRIs)，單胺氧化晦抑制劑(MAOIs)，單胺氧化臃可逆制劑(RIMAs)，血清 素及與正腎上腺素吸收抑制劑(SNRIs)，腎上腺皮質素釋放因子(CRF)拮抗 劑，alpha-adrenoreceptor antagonists及atypical anti-depressants。 合適的正腎上腺素回收抑制劑包含tertiary aminet tricyclics及 secondary amine tricyclics。合適的tertiary amine tricyclics 的例 子包含：amitriptyl ine，clomipramine, doxepin，imipramine及 trimipramine ’及其製藥學上可接受的鹽類》合適的secondary amine tricyclics的例子包含：amoxapine,desipramine，maprotiline， ίο 1324935 nortriptyline及protriptyline，及其製藥學上可接受的鹽類。合適的 選擇性血清素回收抑制劑包含：fluoxetine，fluvoxamine，paroxetine及 sertraline ’及其製藥學上可接受的鹽類。合適的單胺氧化晦抑制劑包含： isocarboxazid，phenelzine, tranylcypromine及selegiline，及其製藥學 上可接受的鹽類。合適的單胺氧化晦可逆抑制劑包含：moclobemide，及其 製樂學上可接受的鹽類。合適的serotonin and noradrenaline reuptake inhibitors在本發明有用到的包含：veniafaxine，及其製藥學上可接受的 鹽類。合適的CRF antagonists包含描述於國際專利編號W0 94/13643號， W0 94/13644號 ’ W0 94/13661 號，W0 94/13676號和W0 94/13677號（在此 所引述的内容係作為參考之用）。合適的atypical anti-depressants包含： bupropion, lithium，nefazodone，trazodone及viloxazine，及其製藥學上 可接受的鹽類。合適的抗焦慮劑類包含benzodiazepines及5-HT1A作用劑或 拮抗劑，尤其5-HT1A partial agonists，及腎上腺皮質素釋放因子 (CRF)括抗劑。合適的benzodiazepines 包含：alprazolam, chlordiazepox ide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepa m及praz印am ’及其製藥學上可接受的鹽類。合適的卜耵丨人接受器作用劑或 拮抗劑包含’尤其是5-HT1A receptor partial agonists buspirone，fles inoxan，gepirone及ipsapirone ’及其製藥學上可接受的鹽類。 額外的治療藥物可為例如，某一抗發炎類固醇，譬如dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide，或其他譬如揭載於美國專利編號2,789,118號，2, 990,401號， 1324935 /， 3,048,581 號，3,126,奶號，3, 929, 768號，3, 996,359號，3, 928,326號及 …”^，在此所引述的美國專利均係作為參考之用。^·^· (Decadron. TM.)特別適宜。 從褪黑激素’其他褪黑激素酿導劑，縫激素作㈣及/或链黑激 素括抗劑’當中選用至少-種複合劑’可以與物理治療合用，如光照療法 或電刺激，例如，安排亮光曝照’暴露於普通光度，或暴露於半夜或黑暗 中。本發明實際應用之一，可在投予本藥時戴深色或紅色眼鏡，以產生與 黑暗的加成作用。另一實際應用，所外加另一治療藥物可為厭食劑，以治 療或預防飲食障礙’例如心因性飲食症或飲食症，因其可能會影響睡眠。 合適的厭食劑有例如 aminorex, amphechloral，amphetamine, benzphetami ne, chlorphent ermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenf luramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetam ine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepr amone, methamphetamine，norpseudoephedrine, pentorex, phendimetrazin e，phenmetrazine，phentermine，phenylpropanolamine, picilorex及 sibutramine。特別適合的厭食劑包含amphetamine及其衍生物，故包含例 如amphetamine, benzphetamine，chlorphentermine，clobenzorex, cloforex , clotermine, dexfenfluramine, dextroamphetamine, diethylpr opion,N-ethylamphetamine,fenfluramine, fenproporex, furfurylmethyl 12 1324935 amphetamine, levamf etamine, mef enorex, metamfepramone, methamphetami ne, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phe ntermine, phenylpropanolamine, picilorex 及 sibutramine〇 —特別適合的 厭食劑類為amphetamine鹵化衍生物，包含chlorphentermine，cloforex， clortermine, dexfenfluramine, fenfluramine, pici lorex及 sibutramine。特別適合的amphetamine鹵化衍生物，可與本發明的複合劑 合併用的，包含：fenfluramine及dexfenfluramine。輔助治療或預防肥胖 症，本發明的複合物也可與選擇性血清素回收抑制劑(SSRI)合用。合適的 選擇性血清素回收抑制劑包含：fluoxetine，fluvoxamine，paroxetine及 sertraline。所有這些複合劑的製藥學上可接受的鹽類，適合時，當然也 包括在内。本發明將以下面數例說明： 例1 方法：以隨機，雙盲’兩平行組研究，研究延長釋放型褪黑激素，在 40位原發性失眠症老年患者（年齡76 [標準誤差8]歲）對睡眠量與質的效 果。患者治療三週，每晚給予褪黑激素（2毫克延_放型试安慰劑。療 程最後兩天’給予鱗整晚喊多電波糊量魏的量。作完實驗室睡眠 電波紀錄義日早上’每絲者都作-套精神運動酿，_量其白天敏 覺隹此外|者每日於日諸上，紀錄其所感受到之前晚的睡眠品質。 果·睡眠之誘導（依入睡前潛伏期⑻，入睡前清醒期⑽卿）， 及入睡前之睦睡時間所佔百分比⑽APOT)測量)使用複黑激素比起使用安 慰劑來有意義地改善.见平均縮短9分鐘(p=〇 〇11)，（腿聊與麵着 13 1324935 也都有意義地改善：（各為ρ=0·011及p=0.02)。關於持續睡眠的變數(醒來 次數，入睡後清醒時間(DWASO)，睡眠效力，全部睡眠時間），就使用褪黑 激素與使用安慰劑兩者之間沒有差別。對於睡眠結構或整夜腦波譜分析， 也無组別之差別。 結論：這些結果顯示，褪黑激素有好的類似安眠劑的啟始睡眠效果。 褪黑激素的安眠效果記載於文獻報告顯示，複黑激素促進人類的睡眠，但 不會改變正常睡眠結構。相對於此明顯催眠效果，患者的精神運動能力， 在褪黑激素治療組’顯著得高於安慰劑治療組：在治療結束時發現到，褪 黑激素治療組相對於安慰劑治療組，在臨界閃光融合測驗及總反應時間， 有顯著的治療效果。 故’這些結果首次顯出’在原發性失眠症患者，褪黑激素的催眠效果(縮 短入睡前潛伏期），合併促進白日的敏覺性，表示這些患者已增進睡眠的恢 復活力值。安眠劑縮短入睡前潛伏期並改善睡眠品質，會併有早晨精神運 動能力損害’或頂多是無顯著惡化。從未有舰雛促進自日敏覺性。令 人驚奇得’在患者日認裡，患者並未評估使職黑激素比起安翻更容易 入睡。事實上’患者判斷’其睡眠品質改善，是因褪黑激素治療，而不是 因安慰劑。故，睡眠之恢復活力值，已合併_眠品質的改善。 例2 方法：以隨機，雙盲，兩平行組研究，研究延長釋放·黑激素，在 Π0位原發性失眠症老年患者(年齡68·5 [標準誤差8 3]歲)對主觀評估睡 眠品質與自日敏覺性的效果。患者先投予兩週安鋪吨絲本特徵，然 二週褪黑激素(延長釋放型每晚2毫克）或安慰劑。在基本特徵與 /。療期間各最後三天的療程，要求患者評估其前晚睡眠品質及其在早晨的 感覺。睡眠品質的題目是，如何比較，有使用藥物時的睡眠品質與沒有 使用藥物(您平常)時的睡眠品f?，患者將其感受_睡眠品質，標記在 、，毫米有標7F兩端的水平無影線上。左端標示〃平常睡得差〃而右端標示， 平常能睡得好，’醒時狀態的題目是，現在覺得如何？〃患者將其感受到 醒時狀態’標記在1GG毫財標示兩韻水平無影線上。左端標示，疲累 ’’而右端標示〃敏覺〃。測量患者的標計，離線右端的絲距離。（值愈 短，表示睡練讀不累）。計算三魏上輯得其平均值。 、”果.結果發現’褪黑激素峡安_丨來，在睡眠品質與白日敏覺性， 都有顯著改善(參閱附件表i )表示，睡得好，與早晨較不疲勞有關。 結論：這些結果顯示’褪黑激素促進原發性失眠症患者睡眠峨復活 力值。 方法.以隨機’雙盲，力平行組研究，研究褪黑激素，在131位原發性 失眠症老年患者(年齡20-80歲)對主觀評估睡眠品質與白日警覺性的效 果。患者先好-週麵_建立基本触，鎌再投予三賴黑激素（延 長釋放型每晚2毫克)絲鋪。在基本概與練最後三天的療 程，要求患者評估其前晚睡眠品質及其在白天的感覺，一如例2 ^ 結果：在55歲或以上的患者，如同在其他的研究裡的老年人一樣，有 改善其睡眠*質及自日敏覺(蝴2) »驚奇地，在擔55歲之患者，比起 15 1324935 安慰劑來，其睡眠品質與白曰敏覺’有顯著的惡化。結果列表於表2(參閱 附件表2)。 結論：老年人較易有維持睡眠及非恢復活力性睡眠的困難，百分之四 十的老年人抱怨睡眠困難，包括易受干擾或"輕"眠，及白日瞌睡 (Vitiello，MichaelGeriatrics Vol. 54(11):47-52 1999)。年輕人典型 地是入睡困難（Roth, Thomas and Roehrs，Timothy Sleep V〇119(8):S48-49 1996)，且其主要困難可能是因睡眠不足，而不是因非恢 復活力性睡眠。這些結果(參閱附件表2)清楚表示，褪黑激素對相關於非 恢復活力性睡眠的原發性失眠有效，但在其它病因的失眠（例如，因無法 入睡導至的睡眠不足）則可能有害。 例4 .方法.研究裙黑激素(2毫克延長釋放型），队队6-1：1^11^1;1171-2-1)~ tolylimidazo[l，2-a]pyridine-3-acetamide(zolpidem; 10毫克）及安慰 劑，在16位建康老年人自願者年齡59.4歲（標準誤差3.2)，對精神運動能 力及駕敬的效果。以隨機，雙盲，交叉研究，患者在晚間先投予一顆安慰 劑以確定基本線，然後以隨機順序在晚間投予一顆褪黑激素，z〇lpidem或 安慰劑，治療一週，在治療當中有間隔一週沒治療。在投予藥物既定的時 間後，讓患者作一套精神運動測驗，駕駛表現，駕駛時的腦波，進行研究。 結果：比起安慰劑來，zolpidem有些急性障礙，此在投予後12.5小時 可缓解。zolpidem的效果，在測量注意力，短暫二次記憶及運動協調時都 可見到。相對於女慰劑與袍黑激素2毫克，z〇ipidem 10毫克導致記憶力， 16 包含兩種U即及延時)均降低。褪黑激賴不㈣作用。 Z〇lpiden Κ)毫克對於駕致表現的變數(絕對速率，偏離速限及偏離理 想路徑）的標準誤差，及撞車次數，有_差別。在投予__ ι〇 毫克後兩小時’絕對速率及偏離速限與理想路徑的標準誤差，確實有增加。 這些標準誤差增加’表示駕驶不規律的不只是速率不穩，連駕馱路線也不 平順。偏離了理想駕馱路線，證實了 z〇lpideml〇毫克組投藥2小時後撞車 次數的增加。而魏驗魏(延長雜型2妓)驗有這樣的後果。 結論：這些研究顯示，患者敘述睡眠品質的改善(就如―池扭組）， 不-定表示促進了恢復活力性魏，@其並未促進白日敏覺。#遍說來， 本例顯示褪黑激素並未改善非失眠症患者的敏覺性。 例5 : 延長釋放型褪黑激素配方製劑。用於例1—例4的延長釋放型口服劑型乃以 丙烯酸樹脂EUdragit(R〇hm藥廠)基底粉塊煉劑直接壓縮調製。褪黑激素(2 毫克；Sygena ’瑞士）與磷酸氫約40毫克與乳糖80毫克在固態狀混合成基 底塊(40毫克£11办38沅1^?0)，此混合物再以2.5噸7毫米圓柱製藥沖床機 壓縮》 以下列出本發明相關的實驗例與功效數據資料，以及本發明與先前技 藝臨床效果之比對： 藉由紀錄夜晚的心理性肌肉運動、衍生自Leeds心理性運動測試系列 (>眠正與清醒）的認知神經測試以及注意力評估測試，來評估失眠症與早 晨的認知能力狀況。治療結束時，一些與失眠相關的評量出現大幅的成效^ 17 1324935 如表Y所示，出現了顯著的效果，臨界閃爍測試（CFF)發現了增加長效釋 放褪黑激素對安慰劑的增加數據(p= 0. 031)。總反應時間（TRT)參數(P= 0.014)中亦發現長效釋放褪黑激素對安慰劑的顯著治療效果’讓我們聯想 到治療後的CNS清醒和反應時間速度改善的狀況（見表Y)° 表Υ 安慰劑 延長釋放效力 的褪黑激素 尸值(超黑激 素對安慰劑) 基線 治療 基線 治療 總反應時 間 (分鐘） 709.5+114.7 704+108.6 654. 7土65.1 635. 6土82.4 0.031 臨界閃爍 融合 _ (頻率） 32.7+3 31. 9+2.8 33.6+3.1 33.8+2.6 0.014 zolpidem是目前世界上最常被醫生指定處方的失眠症藥物，這是種用 來治療睡眠量（增加睡眠潛在因素，減少總睡眠時間）和睡眠品質問題的 樂物’但是並不具改善日間作息表現敏捷度的功能，因此z〇lpidem並未改 善無法提振精神的睡眠狀況。本發明之發明人曾以臨床實驗z〇lpiden^+於原 發性失眠症的效果’由實驗發現zolpidem缺乏改善日間作息表現的效果，而 長效釋放褪黑激素可改善兩項數據的結果，證明了褪黑激素具有改善睡眠品 質的效果。 方法:我們在114名老年原發性失眠症患者（年紀68歲（標準偏差9)) 身上，以隨機研究、雙重盲目、兩平行組的方式，主觀評估z〇lpidem對睡 眠品質和日間作息敏捷度所產生的效果。我們對受測者投以兩星期的安慰 劑’接著給三星期的z〇lpidem (10mg)或安慰劑。 18 1324935 結果：主要效力結果顯示’ zolpidem的確改善了利用lseQ (QOS參數， 〇=0· 002)進行測量的睡眠品質及利用lseQ (GTS參數，〇=〇. 014)進行測 量的睡眠潛伏因素，但z〇lpidem並未明顯影響早晨的警覺敏捷性（班1參 數）（見表X)。1324935 VII. OBJECTS OF THE INVENTION: The present invention relates to a method of treating primary insomnia (as defined by DSM-IV or non-organic insomnia as defined by ICD-10) characterized by non-revitalized sleep, The use of melatonin or other combination agents in the preparations made for this purpose, and a combination of various combination agents to improve the quality and quality of sleep in patients with primary insomnia. BACKGROUND OF THE INVENTION According to the present, the existence of sleep disorders is quite common, and the causes are extremely complicated. Especially in western industrial countries, it is estimated that about one-third of the adult population has at least occasionally have sleep disorders, and at least among these sleep-disabled populations Half of the complaints about sleep disorders have been in existence for several years. In US Patent No. US 5,776,969 (James), there is a specific combination of chemical complexes to treat various sleep disorders; insomnia, discussed in it Non-revitalized sleep may or may not be included in the defined items. Primary insomnia is defined in the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 1994): Most major complaints are difficulty falling asleep or difficult to maintain sleep, or non-rejuvenation Sleep has been at least a month. This sleep disorder (or its combined daytime exhaustion) causes clinically significant distress or damage to its social, professional, or other important functions. What is more, 'as defined here, it is a non-revitalized sleep, and if it causes a dysfunction from the sky, it is enough to establish a diagnosis of primary insomnia. According to the International Classification of Diseases, Tenth Edition (ICD-10) (World Health Organization, 1991), non-invasive insomnia is described as the amount and/or quality of sleep. It also pointed out that although the amount of sleep is within the normal range of subjective and / or objective judgment, there are still people suffering from poor sleep quality. 4 1324935 According to the diagnostic guidelines of ICD-10, the necessary clinical features for the diagnosis of primary insomnia are as follows: a. complaining that it is difficult to sleep, or that it is difficult to sleep, or that sleep quality is low; b. The occurrence of sleep disorders, at least three times a week, and has been one month; c, insomnia at night and from the heart of the heart and excessive anxiety; d, lack of sleep and / or quality ' or cause significant suffering Right, or interfere with social and professional functions. Thus, ICD~10 repeatedly emphasizes that the amount of sleep and the quality of sleep are equally important in lin insomnia. Thus, the invention relates to primary insomnia (DSM_IV) or non-organic insomnia (ICD-10). And because the concentration of the natural hormone melatonin in the blood of normal people is higher than that from night (depending on the specific file, see US Patent No. US 5 498 423 (Zisapel)), and because of the lack of nighttime blackening Hormones are associated with sleep disorders, especially in but not limited to the elderly's feasibility of administering exogenous melatonin to improve sleep disorders. It has been studied and is also a subject in many scientific literature. So 'for example. In James, SP and his peers (Neuropsychopharmacology 1990, 3:19-23), melatonin (1 mg and 5 mg) and placebo, at 1 pm 45 pm, one night each The average age of the insomnia patients who were given 1 sputum to screen for sleep multiple radio waves was 33.4 years old. These patients (although not necessarily non-resorptive sleep-related insomnia) do have a lack of sleep that can be verified by PSG. Administration of melatonin did not alter sleep latency, sleep performance, total sleep time, or wakefulness after falling asleep. The patient's description has improved the quality of sleep, although they did not get more rest in the morning, and they thought that they all had shorter sleep time when using melatonin. In Ellis, CM and colleagues (J. Sleep Res., 1996, 5: 61-65), for patients with psychophysical insomnia, melatonin (5 mg) was administered at 8 o'clock in the evening for a week. No changes were reported in the quality; 8 out of 15 patients could not tell when the period of melatonin treatment was. In addition, in Hughes, RJ· and colleagues (Sleep 1998, 21: 52-68), elderly patients who were unable to continue to sleep insomnia who had been screened by sleep multiple radio waves were immediately released at 3 minutes before bedtime. Type and controlled release of melatonin (0.5 mg and 5 mg), and administered 0.5 mg of the immediate release melatonin formulation midway through the night. They found that both melatonin preparations reduced sleep latency, but did not change the wake-up time after sleep (this is an important variable that does not sustain sleep insomnia) or the total sleep time. They did not find that melatonin has altered sleep quality or mood and sensation during the day. Also, in the MacFarlane JG• and colleagues (Bi〇i pSyChiatry 1991, 30(4): 371-6) report that melatonin (75 mg orally) was administered at 10 o'clock in the evening for 14 consecutive days. The subjective assessment of 13 insomnia patients was considered to have a significant increase in total sleep time and diurnal sensation, but 7/13 of the patients considered no significant effect on subjective comfort. Therefore, from the published literature, there is no evidence to suggest that administration of exogenous melatonin (or other melatonin-like agonist, melatonin agent, or melatonin antagonist) in the present invention Within the scope, patients with primary insomnia who have non-revitalized sleep characteristics may improve the quality of their sleep rejuvenation. However, in contrast to the results of the above published literature, the present inventors have unexpectedly discovered that melatonin 1324935 (and other melatonin-like agonists, melatonin agents, or melatonin antagonists) actually enhances The quality of restoring vitality in patients with primary insomnia. Melatonin agents and melatonin antagonists for use in the present invention include, but are not limited to, U.S. Patent Nos. 5,151,446, 5,318,994, 5,385,944, 5,403,851, and International The compounding agent described in the specification of Patent No. 97/00069. U.S. patents and references cited herein are incorporated by reference. SUMMARY OF THE INVENTION The present invention provides, on the one hand, melatonin, other stick melatonin-like agents, melatonin agents and melatonin antagonists, the effective amount of which is between 25 mg and 5 mg. , wherein at least one compound is selected as a medicament for treating and improving the restorative vitality of sleep in a patient with primary insomnia; and the medicament is also prepared from at least one pharmaceutically acceptable diluent, preservative, antioxidant, It consists of a solvent, an emulsion adjuvant or a carrier. On the other hand, the present invention provides a method for treating or ameliorating the rejuvenating sleep quality of patients with primary insomnia. This method is derived from melatonin, other melatonin-like stimulating agents, melatonin acting agents and blackening. Among the hormone antagonists, at least one compounding agent is used, and an effective dose is administered to the above patient, and the above effective dose is between 0.0025 mg and 5 mg. Still - aspects The present invention provides an agent to improve the quality and quantity of sleep in a patient with primary insomnia. This method is from; black age 'other age class stimuli, melatonin agent and melatonin antagonist when the towel 'at least turn-type compounding agent, and at least add - selected from anxiolytic agents, anti- Inhibitors, hypnotics, sedatives, antihypertensive agents, anti-nocturnal agents, dopamine-induced agents, antipsychotics, sedatives, anorexia agents and anti-inflammatory drugs, effective therapeutic drugs, in addition to 7 1^24935 up to ^ A pharmaceutically acceptable diluent, preservative, antioxidant, solubilizing agent, emulsifying adjuvant or carrier. DETAILED DESCRIPTION OF THE INVENTION The medicament of the present invention or its use is preferably further characterized by at least one of the following characteristics: (I) suitable for oral, anal, injection, oral mucosa, intrapulmonary (eg, inhalation), or Percutaneous administration; cm is a single-volume type; each unit dose consists of at least one of the aforementioned complexes, and the dose is between 0.025 mg and 1 mg; (Π) is a prolonged release formula; (IV) Type 'the accumulation pattern will be in the body, in the pre-selection time, slowly release the aforementioned at least one of the formation; (V) is also added with an additional selected from anxiolytics, dopamine agents, antipsychotics, small towns ' Anaerobic storage and anti-fat "medicine age to _ _ a variety of therapeutic drugs. In the agent provided by the present invention, at least one compound is preferably used at a dose which can improve the quality of restorative vitality of a patient with primary insomnia (as defined above), and at least one additional therapeutic drug. The dose is better to use a dose that increases the amount of sleep in the patient. The method for treating and improving the quality of restorative vitality of sleep in patients with primary insomnia (as defined above) in the present invention is antagonized from melatonin, other melatonin-type cytokines, melatonin acting agents and melatonin Among the agents, at least one compound is used to administer an effective dose, and the method is preferably administered in a dosage form; the dosage form also contains at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizing agent, and emulsification aid. Agent or carrier. 1324935 The agent should be further classified according to at least one of the above characteristics (I), (H), (III) and (IV). The agents relating to the present invention, pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, adjuvants and carriers are conventionally used in pharmaceutical formulations. For oral administration, the agent can be formulated, for example, as a tablet, capsule, emulsion, solution, syrup or suspension. The injection can be made, for example, in the form of a glass ampule, or a suspension, a water-soluble base or an oil-soluble base solution or emulsion. The use of suspending agents, stabilizers and/or dispersing agents will of course take into account their solubility or the solubility of the acting complex in a particular product base. The agent may also contain, for example, physiologically compatible preservatives and antioxidants. The medicament may also be used as a suppository with conventional suppository bases such as cocoa butter or other glycerides. As mentioned above, 'from melatonin, other melatonin-like agents, melatonin agents and melatonin antagonists, at least one compound is used, which can be combined with other complex agents that promote sleep. And (ie, at the same time, separate, or continuous combination). These other complexing agents include, for example, an anti-anxiety, anti-inhibiting agent, a hypnotic agent (benzodiazepine and non-benzodiazepine), a sedative, a hypotensive agent, an analgesic dopamine agent, an antipsychotic agent, a sedative, an anorexia agent. An additional at least one therapeutic agent with an anti-inflammatory drug or the like. Such additional therapeutic agents such as adinazolam, allobarbital, alonimid, alprazolam, amitriptyl ine, amobarbital, amoxapine, bentazepam, benzoctamine, brot izolam, bupropion, busprione, butabarbital, butalbital, capuride, carb ocloral, chloral betaine, chloralhydrate, chlordiazepoxide, clomipr Amine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, de sipramine, dexclamol, diazepam, dichloral phenazone, divalproex, diphe 9 1324935 nhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flu nitrazepam, flurazepam, fluvoxanine, fluoxetine, fosazepam, Glutethim lde, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetaze pam, maproti1ine, mecloqualone, mephobarbital, meprobamate, methaqual one, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortript yline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, Pe rphenazine, phenelzine, phenobarbital, prazepam, promethazine, propof ol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, Ser traline, suproclone, temazepam, thioridazine, tracazolate, tranylcypr omaine, trazodone, triazolam, trepipam, reicetamide, triclofos, triflu operazine, trimetozine, trimipramine, uldazepam, valproate, venlafaxi ne, zaleplon, zolazepam, zolpidem, zopiclone, and its salts Suitable antidepressant classes, including combinations of norepinephrine recovery inhibitors, selective serotonin recovery inhibitors (SSRIs), monoamine osmium oxide inhibitors (MAOIs), monoamine oxime reversible preparations (RIMAs), serum And adrenergic absorption inhibitors (SNRIs), cortisol releasing factor (CRF) antagonists, alpha-adrenoreceptor antagonists and atypical anti-depressants. Suitable norepinephrine recovery inhibitors include tertiary aminet tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics include: amitriptyl ine, clomipramine, doxepin, imipramine and trimipramine 'and their pharmaceutically acceptable salts. Examples of suitable secondary amine tricyclics include: amoxapine, desipramine, maprotiline, ίο 1324935 nortriptyline and Protriptyline, and its pharmaceutically acceptable salts. Suitable selective serotonin recovery inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline' and their pharmaceutically acceptable salts. Suitable monoamine cerium oxide inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof. Suitable monoamine cerium oxide reversible inhibitors include: moclobemide, and its pharmaceutically acceptable salts. Suitable serotonin and noradrenaline reuptake inhibitors useful in the present invention include: veniafaxine, and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include those described in International Patent No. WO 94/13643, W0 94/13644 'W0 94/13661, WO 94/13676 and WO 94/13677 (the contents of which are incorporated herein by reference) use). Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof. Suitable anti-anxiety agents include benzodiazepines and 5-HT1A agents or antagonists, particularly 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include: alprazolam, chlordiazepox ide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepa m and praz im am' and their pharmaceutically acceptable salts. Suitable dilator receptor agents or antagonists comprise, in particular, 5-HT1A receptor partial agonists buspirone, fles inoxan, gepirone and ipsapirone' and pharmaceutically acceptable salts thereof. Additional therapeutic agents can be, for example, an anti-inflammatory steroid such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as U.S. Patent Nos. 2,789,118, 2,990,401, 1324935 /, 3,048,581 , 3, 126, milk number, 3, 929, 768, 3, 996, 359, 3, 928, 326 and ... "^, the US patents cited herein are incorporated by reference. ^·^· (Decadron. TM. ) Particularly suitable. From melatonin 'other melatonin brewing agents, suture hormones (four) and / or chain melatonin anti-agents - at least - a combination of agents can be combined with physical therapy, such as phototherapy or electricity Stimulating, for example, arranging for a light exposure to be exposed to ordinary luminosity, or to exposure to midnight or darkness. One of the practical applications of the present invention may be to wear dark or red glasses when administering the drug to create a darkening bonus. Another practical application, plus another therapeutic agent may be an anorectic agent to treat or prevent a dietary disorder such as a psychogenic disorder or eating disorder, which may affect sleep. Suitable anorectic agents are, for example, aminorex, amphechloral, amphetamine, benzphetami ne, chlorphent ermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenf luramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex , fluminorex, furfurylmethylamphetam ine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepr amone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazin e, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine. Particularly suitable anorectic agents include amphetamine and its derivatives, and thus include, for example, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine, dextroamphetamine, diethylpr opion, N-ethylamphetamine, fenfluramine, fenproporex, furfurylmethyl 12 1324935 amphetamine, levamf etamine, Mef enorex, metamfepramone, methamphetami ne, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phe ntermine, phenylpropanolamine, picilorex and sibutramine〇 - a particularly suitable anorectic agent is an amphetamine halogenated derivative comprising chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, pici Lorex and sibutramine. A particularly suitable amphetamine halogenated derivative, which can be used in combination with the complexing agent of the present invention, comprises: fenfluramine and dexfenfluramine. For the adjuvant treatment or prevention of obesity, the complex of the invention may also be combined with a selective serotonin recovery inhibitor (SSRI). Suitable selective serotonin recovery inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline. The pharmaceutically acceptable salts of all of these complexing agents, as appropriate, are of course included. The present invention will be illustrated by the following examples: Example 1 Method: A randomized, double-blind 'two parallel group study to study extended release melatonin in 40 elderly patients with primary insomnia (age 76 [standard error 8] Years old) on the amount of sleep and quality. The patient was treated for three weeks, and melatonin was given every night (2 mg extended-release type placebo. The last two days of the treatment course) gave the amount of the radio wave volume Wei in the whole night. After the laboratory sleep wave record, the morning of the day Every silker is made - a set of mental sports, _ amount of its daytime sensitivity 隹 | 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者 者, waking up before going to sleep (10), and the percentage of sleepiness before going to sleep (10) APOT) measurements using melatonin compared to using placebo to make a meaningful improvement. See an average reduction of 9 minutes (p = 〇〇 11), (Legs and face 13 1324935 also all meaningfully improved: (each ρ=0·011 and p=0.02). Variables about continuous sleep (wake up, wakefulness after sleep (DWASO), sleep effectiveness, all There was no difference between melatonin and placebo in terms of sleep time. There was no difference in sleep structure or whole-night brainwave analysis. Conclusion: These results show that melatonin has a good similarity. Sleeping effect of sleeping pills The sleeping effect of melatonin is reported in the literature report, and the melatonin promotes human sleep, but does not change the normal sleep structure. Compared with this obvious hypnotic effect, the patient's mental exercise ability is significant in the melatonin treatment group. Higher than placebo treatment group: At the end of treatment, it was found that the melatonin treatment group had a significant therapeutic effect on the critical flash fusion test and the total reaction time relative to the placebo treatment group. 'In patients with primary insomnia, the hypnotic effect of melatonin (shortening the latency before going to bed), combined with the promotion of daytime sensitivity, indicates that these patients have improved the rejuvenation value of sleep. Hypnotics shorten the pre-sleep latency and improve sleep Quality, there will be morning mental exercise impairment [or at most no significant deterioration. There has never been a frigate to promote self-sensitization. Surprisingly] in the patient's day, the patient did not assess the occupational melanin ratio It’s easier to fall asleep when you turn it up. In fact, 'patients judge' the improvement in sleep quality is due to melatonin treatment, not because of safety. Therefore, the rejuvenation value of sleep has been combined with the improvement of sleep quality. Example 2 Method: A randomized, double-blind, two-parallel study to study the prolonged release of melatonin, an elderly patient with primary insomnia in Π0 (age 68·5 [standard error 8 3] years old) for subjective assessment of sleep quality and self-sensing effect. The patient first gave two weeks of Anshun ton silk features, but two weeks of melatonin (extended release type per 2 mg later) or placebo. During the last three days of the basic characteristics and / treatment period, patients were asked to assess their pre-night sleep quality and their feelings in the morning. The topic of sleep quality is how to compare and use drugs. The quality of sleep and the sleep product f when you do not use the drug (you usually), the patient will feel the _ sleep quality, marked in, mm has the level of the 7F at both ends of the line without shadow. The left end of the mark 〃 usually sleeps differently The right end of the mark, usually can sleep well, 'when the state of waking up is, how do you feel now? The sputum patient feels that he is awake when he is marked with a 1GG mark. The left end is marked, tired ’’ and the right end is marked with sensation. Measure the patient's label, the silk distance from the right end of the line. (The shorter the value, the less the sleep is not tired). Calculate the average of the three Weis. "Results. The results found that 'melatonin gorilla _ 丨 ,, in the sleep quality and daytime sensitivity, have significantly improved (see annex table i), said that sleeping well, and less fatigue in the morning. Conclusion: These results Shows that 'melatonin promotes sleep resilience values in patients with primary insomnia. Methods. Randomized 'double-blind, parallel-group study to study melatonin in 131 elderly patients with primary insomnia (age 20- 80 years old) Subjective assessment of sleep quality and day-to-day alertness. Patients first-weekly _ establish basic touch, then sputum to add three lysone (extended release type 2 mg per night) silk shop. With the last three days of treatment, patients were asked to assess their sleep quality before and during the day, as in the case of 2 ^. Results: Patients aged 55 or older, like the elderly in other studies, have Improves sleep quality and self-consciousness (Butterfly 2) » Surprisingly, in the 55-year-old patient, there was a significant deterioration in sleep quality and sputum sensitivity compared to 15 1324935 placebo. Table 2 (see Annex Table 2). Conclusion: Old People are more likely to have difficulty maintaining sleep and non-revitalized sleep. Forty percent of the elderly complain of difficulty sleeping, including being susceptible to interference or "light" sleep, and daytime sleepiness (Vitiello, Michael Geriatrics Vol. 54) (11): 47-52 1999). Young people typically have difficulty falling asleep (Roth, Thomas and Roehrs, Timothy Sleep V〇 119(8): S48-49 1996), and their main difficulty may be due to lack of sleep. Not because of non-revitalized sleep. These results (see Table 2 in the Annex) clearly indicate that melatonin is effective in primary insomnia associated with non-resorptive sleep, but insomnia in other causes (eg, due to inability to fall asleep) To the lack of sleep, it may be harmful. Example 4. Method. Study skirt black hormone (2 mg extended release type), team 6-1:1^11^1;1171-2-1)~ tolylimidazo[l,2 -a]pyridine-3-acetamide (zolpidem; 10 mg) and placebo, in the 16-year-old Jiankang elderly volunteers age 59.4 years (standard error 3.2), the effect on mental exercise ability and respect. To random, double Blind, crossover study, patients were given a placebo at night to determine This line, then in a random order in the evening to give a melatonin, z〇lpidem or placebo, treatment for one week, there is no treatment in the interval between treatments. After the given time of administration of the drug, let the patient make a set of spirits Exercise test, driving performance, brainwaves during driving, study. Results: zolpidem has some acute disorders compared with placebo, which can be relieved 12.5 hours after administration. The effect of zolpidem, measuring attention, short secondary memory And can be seen when the movement is coordinated. Compared to the feminine and robe melanin 2 mg, z〇ipidem 10 mg leads to memory, 16 contains both U and delay). Blackness does not affect (four). Z〇lpiden Κ) milligrams have a difference in the standard deviation of the driver's performance variables (absolute rate, deviation from the speed limit and deviation from the ideal path), and the number of crashes. Two hours after the administration of __ ι〇 mg, the absolute error and the standard deviation of the deviation from the ideal path did increase. These standard error increases indicate that the driving is not just the rate instability, and the driving route is not smooth. Deviation from the ideal driving route confirmed the increase in the number of crashes in the z〇lpideml〇 mg group after 2 hours of administration. Wei Weiwei (prolonged miscellaneous 2妓) has such consequences. Conclusions: These studies have shown that patients have an improvement in sleep quality (as in the “Chip-Twist group”), which does not contribute to the rejuvenation of Wei, which does not promote daytime sensitivity. #遍说, This example shows that melatonin does not improve the sensitivity of patients with non-insomnia. Example 5: Extended release melatonin formulation. The extended release oral dosage form used in Examples 1 to 4 was directly compression-modified with an acrylic resin EUdragit (R〇hm Pharmaceuticals) base powder bulk refining agent. Melatonin (2 mg; Synage 'Swiss) is mixed with hydrogen phosphate about 40 mg and lactose 80 mg in solid form into a base block (40 mg £11 for 38 沅1^?0), and this mixture is again 2.5 ton 7 mm Cylindrical Pharmaceutical Punch Press Compression The following is a list of experimental and efficacy data related to the present invention, and the comparison of the present invention with the prior art clinical effects: by recording the psychological muscle movement at night, derived from the Leeds psychological exercise test series Cognitive neurological tests and attention assessment tests (> sleep positive and awake) to assess insomnia and morning cognitive status. At the end of treatment, some assessments related to insomnia have shown significant results^ 17 1324935 As shown in Table Y, significant effects have emerged, and the Critical Scintillation Test (CFF) has found an increase in long-acting release of melatonin to placebo. Data (p = 0. 031). The significant response time of long-acting release of melatonin to placebo was also found in the total response time (TRT) parameter (P = 0.014), which reminds us of the improvement in CNS awake and response time after treatment (see Table Y). ° Table Υ Placebo prolonged release of melatonin physiology (superelegin versus placebo) Baseline treatment Base treatment total response time (minutes) 709.5+114.7 704+108.6 654. 7 soil 65.1 635. 6 soil 82.4 0.031 critical Flicker fusion _ (frequency) 32.7+3 31. 9+2.8 33.6+3.1 33.8+2.6 0.014 zolpidem is currently the most commonly prescribed insomnia drug in the world, which is used to treat sleep (increased sleep potential) , to reduce the total sleep time) and the quality of sleep problems, but does not improve the performance of daytime performance, so z〇lpidem did not improve the sleep state that can not boost the spirit. The inventors of the present invention have used the clinical experiment z〇lpiden^+ in the effect of primary insomnia' to find that zolpidem lacks the effect of improving daytime performance, and long-acting release of melatonin can improve the results of two data. It has been shown that melatonin has an effect of improving sleep quality. METHODS: We prospectively assessed z〇lpidem for sleep quality and daytime agility in 114 elderly patients with primary insomnia (age 68 (standard deviation 9)) in a randomized, double-blind, two-parallel group. The effect produced by the degree. We administered a two-week placebo to the subjects' followed by three weeks of z〇lpidem (10 mg) or placebo. 18 1324935 Results: The main efficacy results showed that 'zolpidem did improve the sleep quality measured using lseQ (QOS parameter, 〇=0·002) and the sleep latency factor measured using lseQ (GTS parameter, 〇=〇. 014), However, z〇lpidem did not significantly affect the morning alertness (class 1 parameter) (see Table X).
Zolpidem mm單位中數變 化（SE) 安慰剤 mm單位中數變化（SE) P值 (Zolpidem 對安慰劑) 睡眠感知品質的 變化 -25· 9 (2. 9)* -12.9 (2.8) 0.002 睡眠感知潛在因 素的變化 -21.1 (2.7)木 -11.9 (2.4) 0. 014 曰常作息敏捷度 感知變化 -16.3 (3.0) -11.4 (2.3) 0.2 •安慰劑的差異相當明顯（p<〇. 〇5) 結論··試驗結果同意此藥物的一般醫藥資訊，換言之，zolpidem會降 低睡眠潛伏因素，不會惡及日間作息，但也不會改善日間作息敏捷性。紀 錄顯示，zolpidem對改善睡眠品質有幫助，這項結果和投藥10呢劑量給病 患所得到的成效結果一致。因此利用LSEQ評估工具取得的s〇lpidein效果 結果’符合投藥ZC)lpidem 1〇呢所會產生效果的一般醫藥資訊，且符合 zolpidem對曰間作息表現缺乏正面影響的論點。 請比對本發明之長效釋放褪黑激素以相同臨床實驗參數所得結果：（見 下頁表Z) 19 1324935 表z 長效釋放褪黑激素 皿1單位中數變化(SE) 安慰命J 画單位中數變化(SE) 尸值（長效 素對安慰 劑) 睡眠感知品 質的變化 -22.5 (2.3)* -16.5 (1.9) 0.047 睡眠感知潛 在因素的變 化 -14.5 (2.2) -14.1 (1.8) 0.90 曰常作息敏 捷度感知變 化 -15.7 (2.2)* -6.8 (1.7) 0.002 •安慰劑的差異相當明顯（p<〇. 〇5) 以下為另外-項由Neurim (藥廠）對2 mg長效釋放褪黑激素所進行的 實驗’證明褪黑激素具有改善睡眠品質和日㈣息敏捷度表現的結合效果。 方法：在334名老年（年紀65.7歲，（標準偏差6 4))原發性失眠症患 者身上投藥長效釋放鍵激素2mg ’以賴研究、雙重盲目、醉行組的方 式’主觀評估其對睡眠品質和日間作息敏捷度狀況所產生的效力。我們對 受測者投兩星期的安删，接著給三星_長效釋放褪黑激素2呢或安 慰劑。（睡眠評估的結果說明見下頁表1) 20 1324935 表1 ;回應者分析大於等於l〇唧QOS和BFW的進步 -—---------;----- 安慰劑 -- PR褪黑數素2 _ Leeds Q0S 和 BFW 刻度 是 否 卡方檢定 p值治療 L 丨丨 ' —— 上有大於等次 25 (28%) 63 (72 %) l 10mm的進步 ' 36 (47%) 41 (53%) χ2(2)=5.93 ρ=0.015 結果··我們注意到主要端點有明顯差異，如10咖定義的進步或Leeds QOS和BFW兩項參數顯示的更大進步。在長效釋放植黑激素~2呢組中，兩 項參數皆有進步的受測者比例幾乎是安慰劑组的兩倍(p=〇. 014 ,見表2)。 表2 :回應者分析大於等於10mm Q0S和BFW的進步 安慰劑 PR褪黑激素2败 Leeds QOS和BFff刻度上有大於等於1〇瞧的進步 1一- 是 25 (15%) 44 (26%) 否 139 (85 %) 124 (74%) 卡方檢定 χ2(2)=6· 04 ρ=0.014 p值治療 結論·棍黑激素效力結果的臨床關聯’應藉由睡眠品質和日間作息運 作兩者的臨床明顯進步來加以確認。因此，研究中的效力變化乃由於長效 釋放褪黑激素2mg和安慰劑组回應者率而來，如Q〇s和LSEQ的BFW兩項參 數所定義的10 mm或以上的進步改善。這項研究證實，利用長效釋放複黑 激素進行治療，回應出來的結果是睡眠品質和日間作息皆出現有益的改 變。長效釋放播黑激素組與安慰劑組相較之下，其明顯高過的反應率建立 21 1324935 起觀察效S的臨細雛》這些結果和先前的臨糾究結絲示長效釋放 袍黑激素疋第一個在統汁上被證明，在睡眠品質和以日間作息運作改善狀 況加以追縱的潛在ϋ素上、會產生明顯且臨床獅進步的魏症藥物。 本發明某些特殊具象部份特於上述，但本發明不止限於如此，因為内 行人顯然知道能作各種修訂或變化。這些修訂或變化雖未在此詳述，但應 顯然認為相當於本發明。 附件：表1及表2 22Zolpidem mm unit median change (SE) Consolation 剤 mm unit median change (SE) P value (Zolpidem vs placebo) Changes in sleep perception quality -25. 9 (2. 9)* -12.9 (2.8) 0.002 Sleep perception Changes in latent factors -21.1 (2.7) Wood -11.9 (2.4) 0. 014 Changes in adolescents' agility perception -16.3 (3.0) -11.4 (2.3) 0.2 • The difference in placebo is quite obvious (p<〇. 〇5 Conclusion·· The test results agree with the general medical information of this drug. In other words, zolpidem will reduce sleep latency factors, will not be harmful to daytime work, but will not improve daytime work agility. The records show that zolpidem is helpful in improving sleep quality, and this result is consistent with the results obtained with the dose of 10 doses. Therefore, the s〇lpidein effect obtained by the LSEQ evaluation tool is consistent with the general medical information of the effect of the drug lacide 1 ) ide ide , , , , , 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Please compare the results of the long-acting release melatonin of the present invention with the same clinical experimental parameters: (see Table Z on the next page) 19 1324935 Table z Long-acting release melatonin dish 1 unit median change (SE) Comforting J painting unit Median change (SE) corpse value (long-acting hormone versus placebo) Changes in sleep perception quality -22.5 (2.3)* -16.5 (1.9) 0.047 Changes in sleep perception potential factors -14.5 (2.2) -14.1 (1.8) 0.90曰Permanent agility perception change-15.7 (2.2)* -6.8 (1.7) 0.002 • The placebo difference is quite obvious (p<〇. 〇5) The following is another item--Neurim (pharmaceutical) long-term effect on 2 mg The experiment of releasing melatonin demonstrated that melatonin has a combined effect of improving sleep quality and daily (4) agility. METHODS: 334 elderly (65.7 years old, (standard deviation 64)) patients with primary insomnia were administered long-acting release hormone 2 mg 'subjectively, double blind, drunk group' subjective assessment of their The effectiveness of sleep quality and daytime agility. We voted for two weeks for the testee, and then gave Samsung _ long-term release of melatonin 2 or placebo. (The results of the sleep assessment are shown in Table 1 on the next page.) 20 1324935 Table 1; Responders analyzed the progress of greater than or equal to l〇唧QOS and BFW-----------;----- placebo- - PR melatonin 2 _ Leeds Q0S and BFW scale whether chi-square test p-value treatment L 丨丨' —— there is greater than equal time 25 (28%) 63 (72 %) l 10mm progress ' 36 (47% 41 (53%) χ2(2)=5.93 ρ=0.015 Results · We noticed significant differences in the main endpoints, such as the progress of the 10 coffee definition or the Leeds QOS and BFW parameters show greater progress. In the long-acting release of melatonin-2, the proportion of subjects with improved parameters was almost twice that of the placebo group (p=〇. 014, see Table 2). Table 2: Responder analysis greater than or equal to 10mm Q0S and BFW progressive placebo PR melatonin 2 defeated Leeds QOS and BFff scales have an improvement of 1〇瞧 or more 1 - is 25 (15%) 44 (26%) No 139 (85%) 124 (74%) Chi-square test χ 2 (2) = 6 · 04 ρ = 0.014 p-treatment conclusions · Clinical relevance of stick melanin efficacy results should be operated by sleep quality and daytime work The clinical progress has been confirmed to confirm. Therefore, the change in efficacy in the study was due to the long-acting release of melatonin 2 mg and the placebo group responders, such as the improvement of 10 mm or more as defined by the BFW parameters of Q〇s and LSEQ. The study confirmed that the response to long-acting release of melatonin responded to a beneficial change in sleep quality and day-to-day work. Compared with the placebo group, the long-acting release of the melanocortin group has a significantly higher response rate, and the results are as follows: 21 1324935 to observe the effect of S. The results and the previous observations and knots show long-lasting release gowns. The first serotonin sputum has been proven in the juices, and it has obvious and clinically lion-promoting Wei disease drugs in the quality of sleep and the potential remedies for day-to-day work and improvement. Some specific features of the invention are described above, but the invention is not limited thereto, as it will be apparent to those skilled in the art that various modifications and changes can be made. These revisions or variations are not described in detail herein, but should obviously be considered equivalent to the present invention. Accessories: Table 1 and Table 2 22