TW201536282A - 治療抑鬱症之迪米拉西坦（ｄｉｍｉｒａｃｅｔａｍ） - Google Patents
治療抑鬱症之迪米拉西坦（ｄｉｍｉｒａｃｅｔａｍ） Download PDFInfo
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- TW201536282A TW201536282A TW103124837A TW103124837A TW201536282A TW 201536282 A TW201536282 A TW 201536282A TW 103124837 A TW103124837 A TW 103124837A TW 103124837 A TW103124837 A TW 103124837A TW 201536282 A TW201536282 A TW 201536282A
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Abstract
本發明揭示迪米拉西坦(Dimiracetam)或其溶劑化物，其係適用於治療及/或預防抑鬱症之有效物質。
Description
本申請案主張2013年7月24日申請之瑞士專利申請案1306/13之優先權，其揭示內容以全文引用之方式併入本文中。
本發明係關於一種名為迪米拉西坦(Dimiracetam)之有效物質，及用於治療精神病症(特定言之抑鬱症)之包含該有效物質之組合物。
抑鬱症係一種發生在所有性別、年齡及背景之人群的常見精神病症，影響全世界約1.21億人。抑鬱症之症狀包括(但不限於)情緒抑鬱、缺乏興趣或樂趣、內疚或自卑、睡眠紊亂或食慾不振、低能量及注意力不集中或其任何組合。該等問題可變成慢性或復發性且導致個體照顧其日常責任之能力的實質性受損。
抑鬱症之社會重要性可由帶殘疾生命年數(YLD)及/或殘疾調整生命年數(DALY；即因過早死亡率而損失之潛在生命年數與因殘疾而損失之生產生命年數之總和)度量。在2000年時，抑鬱症係如由YLD所測得之殘疾之首要原因，及係如由DALY所測得之全球疾病負擔之第四主要原因。到2020年，預計抑鬱症將達到針對所有年齡的男性女性所計算之DALY之排名的第二位。如今，抑鬱症已成為結合兩種性別之15至44歲年齡類別之DALY的第二原因。雖然明顯地存在很多目前可用的針對抑鬱症之治療，但是顯著比例之患者係經不完全治療
(許多殘留症狀仍存在)，或對治療無任何反應。因此需要抑鬱症之新穎治療。
益智劑係具有很少副作用及極低毒性之認知增強劑。這使它們成為極需之有效物質。西坦(racetam)族成員共享吡咯啶酮核，即：
還沒有針對西坦族之行為的一般可接受之機制。西坦族之一，奈非西坦(nefiracetam)據報告作為抗抑鬱劑。這也係唯一已知在奈莫耳濃度範圍內對毒蕈鹼受體表現親和力之西坦族。儘管有效性較低，其他西坦族為阿尼西坦(aniracetam)及奈拉西坦(nebracetam)(參見http：//en.wikipedia.org/wiki/Racetam)。
奈非西坦係具有下式之化合物：
在WO 2007/104035中，益智劑被描述為用於治療若干種疾病(其中之一為抑鬱症)之藥劑。在其他化合物中，西坦族被建議為合適藥劑，但僅明確提及吡拉西坦(piracetam)與抑鬱症之治療有關，儘管並非任一實例之主體。
因此，本發明之一般目標為提供一種具有低副作用及低毒性之用於治療及預防抑鬱症之強有效物質。
本發明之另一目標為提供一種醫藥組合物，其包含用於治療或
預防抑鬱症之該有效物質。
本發明之又一目標為提供一種用於治療或預防抑鬱症之方法。
本發明之再一目標為提供一種用於治療或預防抑鬱症之製造物品。
現已發現迪米拉西坦係一種良好的抗抑鬱劑。
迪米拉西坦已知為西坦族藥物中之益智劑且已針對其在治療神經性疼痛及認知障礙之作用進行描述。迪米拉西坦為具有下式之化合物：
迪米拉西坦與其他西坦族藥物成員之不同在於它是二環且因此在空間上比其他家族成員靈活性更小。
現已發現迪米拉西坦係一種比西坦族藥物其他成員優越的抗抑鬱劑。
當考慮到以下之本發明詳細描述，可更好地理解本發明且除彼等上述描述之目標外之目標將變得顯然。該描述參考說明以下結果之附圖：圖1：大鼠Porsolt測試，急性；一組8隻大鼠，在投與藥物30分鐘之後測量活動性時間(*：P<0.05；**：P<0.01)。
圖2：大鼠Porsolt測試，10天重複之每日兩次投與；一組8隻大鼠，在投與藥物60分鐘之後測量活動性時間(*：P<0.05；**：P<0.01)。第一慢性測試。
圖3：大鼠Porsolt測試，10天重複之每日兩次投與；一組12隻大鼠，在投與藥物60分鐘之後測量活動性時間(*：P<0.05；**：P<0.01)。第二慢性測試。
圖4：小鼠Porsolt測試，急性；每組19至27隻小鼠，ip(經腹腔內)或po(口服，經口)測試迪米拉西坦且在投與藥物30分鐘之後評估活動性時間(*：P<0.05；**：P<0.01)。
迪米拉西坦在治療抑鬱症中之作用已於動物模型中進行研究，尤其係所謂的Porsolt測試(Porsolt RD、Bertin A、Jalfre M.(1977).「Behavioral despair in mice：a primary screening test for antidepressants」。Archives Internationales de Pharmacodynamie et de Therapie 229(2)：327-336)。該測試亦被稱為行為絕望測試或強制游泳測試。Porsolt測試係用於測量抗抑鬱劑藥物對實驗室動物(代表性地為大鼠或小鼠)之作用的測試。
除了阿密曲替林(amitriptyline，一種在本申請案展示之實驗中作為參考化合物的已知抗抑鬱劑)以外，在所有測試之西坦族衍生物中只有迪米拉西坦在急性與慢性兩種試驗中藉由顯著提高大鼠之活動性時間顯示出抗抑鬱劑活性。
用於本文中的術語迪米拉西坦無論什麽情況下均包括R型及S型對映異構體之任何組合，尤其係外消旋物及單離的純對映異構體，每一個呈該物質本身或呈醫藥上可接受溶劑化物。
本發明亦提供一種治療人類抑鬱症之方法，其包括向有此需要的人投與治療上有效量之迪米拉西坦。
術語「治療上有效量」係指足以調控所治療病況或疾病之一個或多個症狀時的化合物量。
本發明提供一種醫藥組合物，其包含迪米拉西坦或其醫藥上可
接受之溶劑化物及醫藥上可接受之媒劑、佐劑、載劑或稀釋劑。
根據本發明之化合物可藉由任何途徑投與，包括(但不限於)經口、肌肉內、皮下、鼻內、靜脈內、舌下或直腸內。在本發明之一實施例中，投與之途徑可為經口、靜脈內或肌肉內。
為了自本發明之化合物製備之醫藥組合物，惰性、醫藥上可接受之媒劑或載劑可為固體或液體。固型製劑包括粉末、錠劑、可分散顆粒、膠囊、扁囊劑及栓劑。固體媒劑或載劑可為一種或多種物質，其亦可充作稀釋劑、矯味劑、增溶劑、潤滑劑、懸浮劑、黏結劑或錠劑崩解劑。在粉末中，媒劑或載劑為細分固體，其與細分活性組分呈混合物。在錠劑中，將迪米拉西坦與具有必要結合性之媒劑或載劑以合適比例混合並壓縮成所需之形狀及尺寸。
在本說明書之範圍中，固體載劑意欲包括適用於例如提供膠囊之封裝物質，在該膠囊中活性組分(含有或不含其他載劑)被封裝物質包圍因此封裝物質與其締合。相似地，扁囊劑係包含在可能的載劑中。
為了製備栓劑組合物，首先將低熔點蠟諸如脂肪酸甘油酯及可可油之混合物熔化及藉由例如攪拌將活性成分分散在其中。隨後，將熔融之均勻混合物倒入尺寸方便的模具中且容許冷卻及固化。
合適之媒劑或載劑為碳酸鎂、硬脂酸鎂、滑石、乳糖、糖、果膠、糊精、澱粉、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可油及類似物質。
錠劑、粉末、扁囊劑及膠囊可用作適用於口服之固體劑型。
液型組合物包括溶液、懸浮液及乳液。可提及活性化合物之無菌水或水-丙二醇溶液可作為適用於非經腸投與之液體製劑之一實例。液體組合物亦可於水聚乙二醇水溶液中進行調配。用於口服之水溶液可藉由將活性組分溶解於水中並按需要加入合適之著色劑、矯味
劑、穩定劑及增稠劑來製備。用於經口使用之水性懸浮液可藉由將細分活性組分連同黏性物質諸如天然合成膠、樹脂、甲基纖維素、羧甲基纖維素鈉及醫藥調配技術已知之其他懸浮劑分散於水中從而製得。
迪米拉西坦亦可用於預防，例如治療先前患有抑鬱症之人或有遺傳患病體質之人。
醫藥組合物可呈單位劑型。在該形式中，將組合物分為包含合適量之活性組分之單位劑量。單位劑型之實例為膠囊、扁囊劑或錠劑。
劑量將取決於投與途徑、疾病之嚴重程度、患者之年齡及體重、及主治醫師針對特定患者確定最合適之個體療法及劑量程度時通常所考慮之其他因素。
在本發明之範圍中，亦即在所提出之治療中，若經由會達成合適血液含量之所提供任一途徑投與，通常可發揮迪米拉西坦之作用。合適之血液含量被認定為在約50至約750微莫耳濃度範圍中。
迪米拉西坦本身或呈溶劑化物之合適每日劑量之範圍為：用於口服，約1至約100mg/kg，較佳地約8至約70mg/kg，尤其約15至約65mg/kg；或用於肌肉內投與，約5至約25mg/kg，尤其約8至約20mg/kg；或用於靜脈內投與，約2至約20mg/kg，尤其5至20mg/kg；或用於直腸投與，約8至約70mg/kg，較佳地10至65mg/kg，尤其15至35mg/kg。
本文件中，術語「約」意指其所修飾數值之±10%。例如，「約100」意指90至110。
若需要，一部分劑量可由一種途徑投與且另一部分由另一種途徑投與，例如若需要時，可經靜脈內投與固定之部分劑量而經口投與可變化之部分劑量。
單位劑量可按慣例一天投與一次或更多次。
藥物適合調製為每日投與：口服情況下，50至4000mg，較佳地250至3200mg，更佳地400至2500mg；肌肉內投與情況下，200至1200mg，較佳地400至1000mg；靜脈內投與情況下，50至1000mg，較佳地從200至800mg；或直腸投與(以栓劑之形式)情況下，400至3500mg，較佳地為至多3200mg且更佳地800至1600mg。
以mg為單位之每日劑量係參考50kg之平均患者體重。
較佳的範圍匯總於下表1中：
包含迪米拉西坦之醫藥組合物可方便地調配為用於口服之錠劑、藥丸、膠囊、糖漿、粉末或顆粒；用於非經腸投與之無菌非經腸或皮下溶液、懸浮液；或用於直腸投與之栓劑；其所有都為相關技術所熟知。
對於臨床使用而言，迪米拉西坦經調配為用於口服、直腸、非經腸或任何其他投與形式之醫藥調配物。醫藥調配物包含迪米拉西坦與一種或多種醫藥上可接受之成分之組合。載劑可為固體、半固體或
液體稀釋劑或膠囊之形式。該等醫藥製劑係本發明之另一目標。取決於投與模式，醫藥組合物可包含約0.05重量%至約99重量%(重量百分比)、或約0.05重量%至約80重量%、或約0.10重量%至約70重量%、或約0.10%至約50重量%之活性成分，所有重量百分比係基於總組合物計。活性成分可為單獨的迪米拉西坦或迪米拉西坦與一種或多種其他醫藥上有效化合物。
在製備用於口服之呈劑量單位之形式包含迪米拉西坦之醫藥調配物時，迪米拉西坦可與固體、粉末狀成分或另外合適的成分混合，以及可與崩解劑及潤滑劑混合。隨後將混合物處理成為顆粒或壓製成為錠劑。
迪米拉西坦可經調配為軟明膠膠囊或硬明膠膠囊，其包含迪米拉西坦本身，例如呈顆粒或其可包含迪米拉西坦與固體粉末狀成分之組合。直腸投與之劑量單位可呈以下形式製備：(i)呈栓劑之形式，其包含與中性脂肪基質混合之迪米拉西坦；(ii)呈明膠直腸膠囊之形式，其包含與用於明膠直腸膠囊之合適媒劑混合之迪米拉西坦；(iii)呈現成微型灌腸劑之形式；或(iv)呈乾微型灌腸劑調配物之形式，待緊接投與之前在合適溶劑中復水。
用於口服的液體製劑可呈糖漿或懸浮液，例如含有迪米拉西坦之溶液或懸浮液之形式製備。若需要，該液體製劑可包含著色劑、矯味劑、糖精及羧甲基纖維素或其他增稠劑。用於口服之液體製劑亦可呈乾粉(以待在使用之前與合適溶劑復水)之形式製備。
用於非經腸投與之溶液可呈迪米拉西坦在醫藥上可接受之溶劑中之溶液製備。該等溶液亦可包含穩定成分及/或緩衝成分且以安瓿或小瓶之形式分散至單位劑量中。用於非經腸投與之溶液亦可被製備為乾製劑以待在使用之前臨時地與合適溶劑復水。
由於在老年人中抑鬱症可伴隨其他疾病發生尤其係認知能力衰
退且精神及行動兩者減緩，及/或由於抑鬱症可與中風、心血管疾病、帕金森氏病及肺病(只提及一些實例)共存，迪米拉西坦可與其他抗抑鬱劑或改善精神及/或物理效率之藥物呈組合療法進行投與。組合其中迪米拉西坦或其醫藥上可接受之溶劑化物、或包含迪米拉西坦或其溶劑化物之醫藥組合物或調配物可合併地、同時地、依序地或單獨地進行投與。可與迪米拉西坦組合使用之其他化合物可選自以下：(i)抗抑鬱劑諸如阿戈美拉汀(agomelatine)、阿密曲替林、阿莫沙平(amoxapine)、安非他酮(bupropion)、西肽普蘭(citalopram)、氯米帕明(clomipramine)、地昔帕明(desipramine)、多慮平(doxepin)、度洛西汀(duloxetine)、艾扎索南(elzasonan)、依他普蘭(escitalopram)、氯伏沙明(fluvoxamine)、氟西汀(fluoxetine)、吉吡隆(gepirone)、丙米嗪(imipramine)、伊沙匹隆(ipsapirone)、馬普替標(maprotiline)、去甲替林(nortriptyline)、奈法咗酮(nefazodone)、帕羅西汀(paroxetine)、苯乙肼(phenelzine)、普羅替林(protriptyline)、雷美替胺(ramelteon)、瑞波西汀(reboxetine)、羅巴佐坦(robalzotan)、舍取林(sertraline)、西步曲明(sibutramine)、硫異西汀(thionisoxetine)、反苯環丙胺(tranylcypromine)、查諾頓(trazodone)、曲米帕明(trimipramine)、文拉法辛(venlafaxine)；(ii)非典型抗精神病藥，包括例如喹硫平(quetiapine)及鋰。
(iii)抗精神病藥，包括例如首利安(amisulpride)、阿力哌唑(aripiprazole)、阿塞那平(asenapine)、苯異西地(benzisoxidil)、聯苯蘆諾(bifeprunox)、卡巴咪嗪(carbamazepine)、氯氮平(clozapine)、氯丙嗪(chlorpromazine)、地苯紮平(debenzapine)、雙丙戊酸鈉(divalproex)、艾司左匹克隆(eszopiclone)、氟哌丁苯(haloperidol)、伊潘立酮(iloperidone)、拉莫三嗪(lamotrigine)、洛沙平(loxapine)、美索逹嗪(mesoridazine)、奧氮平(olanzapine)、帕立哌酮(paliperidone)、哌
拉平(perlapine)、奮乃靜(perphenazine)、吩噻嗪(phenothiazine)、苯基丁基哌啶(phenylbutylpiperidine)、哌咪清(pimozide)、丙氯陪拉辛(prochlorperazine)、利螺環酮(risperidone)、色吲哚(sertindole)、舒必利(sulpiride)、舒普羅酮(suproclone)、舒立克隆(suriclone)、硫代利噠(thioridazine)、三氟啦嗪(trifluoperazine)、三甲氧啉(trimetozine)、丙戊酸鹽(valproate)、丙戊酸(valproic acid)、佐匹克隆(zopiclone)、澤坦平(zotepine)、齊拉西酮(ziprasidone)；(iv)抗焦慮藥，包括例如阿奈螺酮(alnespirone)、氮哌酮(azapirone)、苯并二氮呯(benzodiazepine)、巴比妥酸鹽(barbiturate)諸如阿地唑侖(adinazolam)、三唑安定(alprazolam)、巴利西泮(balezepam)、苯他西泮(bentazepam)、溴西泮(bromazepam)、溴替唑侖(brotizolam)、鹽酸丁螺環酮(buspirone)、氯硝西泮(lonazepam)、氯氮(clorazepate)、利眠寧(chlordiazepoxide)、環丙西泮(cyprazepam)、地西泮(diazepam)、苯海拉明(diphenhydramine)、艾司唑侖(estazolam)、非諾班(fenobam)、氟硝安定(flunitrazepam)、氟胺安定(flurazepam)、磷安定(fosazepam)、勞拉西泮(lorazepam)、氯甲西泮(lormetazepam)、甲丙胺酯(meprobamate)、咪唑安定(midazolam)、硝基安定(nitrazepam)、奧沙西泮(oxazepam)、普拉西泮(prazepam)、夸西泮(quazepam)、瑞氯西泮(reclazepam)、曲卡唑酯(tracazolate)、曲匹泮(trepipam)、替馬西泮(temazepam)、三唑侖(triazolam)、烏達西泮(uldazepam)、唑拉西泮(zolazepam)；(v)抗驚厥劑，包括例如卡巴咪嗪(carbamazepine)、丙戊酸鹽(valproate)、拉莫三嗪(lamotrogine)、加巴噴丁(gabapentin)、普加巴林(pregabalin)、托吡酯(topiramate)、拉科醯胺(lacosamide)、胺己烯酸(vigabatrin)、噻加賓(tiagabine)；(vi)用於阿茲海默氏病治療之藥物，包括例如多奈哌齊
(donepezil)、美金胺(memantine)、他克林(tacrine)、卡巴拉汀(rivastigmine)、加蘭他敏(galantamine)；(vii)用於帕金森氏病治療之藥物，包括例如左旋多巴(L-dopa)、羅匹尼羅(ropinirole)、普拉克索(pramipexol)、MAOB之抑制劑諸如沙芬醯胺(safinamide)、丙炔苯丙胺(selegiline)及雷沙吉蘭(rasagiline)，CMOT抑制劑諸如恩他卡朋(entacapone)或托卡朋(tolcapone)，A-2抑制劑諸如伊曲茶鹼(istradefylline)、多巴胺(dopamine)再吸收抑制劑，NMDA拮抗劑諸如金剛胺(amantidine)、菸鹼促效劑、多巴胺促效劑及中性一氧化氮合酶之抑制劑；(viii)用於偏頭痛治療之藥物，包括例如阿莫曲坦(almotriptan)、布他比妥(butalbital)、氯醛比林(dichloralphenazone)、依立曲坦(eletriptan)、夫羅曲坦(frovatriptan)、納拉曲坦(naratriptan)、利扎曲坦(rizatriptan)、舒馬普坦(sumatriptan)及佐米曲坦(zolmitriptan)。
該等組合物產品使用本文描述之劑量範圍內之本發明之化合物及在經核准之劑量範圍內之其他醫藥活性化合物。
本發明之另一目標為製造物品，其包括技術方案8至10中任一項之醫藥組合物、容器或包裝及書面說明及投與指示諸如包裝插頁。於一較佳實施例中，醫藥組合物係呈一個或較佳地若干個單位劑量，諸如若干個錠劑、膠囊及裝入小瓶或安瓿之粉末，或裝入小瓶或安瓶之溶液，或即可使用注射器(僅提及一些實例)之形式。
實驗部分：
行為絕望測試(亦稱為Porsolt測試或強制游泳測試)係一個用於測量抗抑鬱劑藥物對實驗室動物(代表性地為大鼠或小鼠)行為之作用的測試。
所有試驗均依照針對實驗室動物照料之1986年11月24日之歐洲共同體理事會指令(European Communities Council
Directive)(86/609/EEC)而進行。所有努力均為使所使用動物之數量及其痛苦最小化。
實例1：迪米拉西坦於小鼠中之評估
該測試係依照Porsolt RD、Bertin A、Jalfre M.(1977)「Behavioral despair in mice：a primary screening test for antidepressants」。Archives Internationales de Pharmacodynamie et de Therapie 229(2)：327-336)而執行。
使用來自Morini養殖場(San Polo d’Enza,RE,Italy)之雄性Swiss Webster小鼠(25至28g)。
本測試之結果記錄於圖式4中。
實例2：迪米拉西坦於大鼠中之評估，與其他西坦族衍生物比較
使用來自Harlan養殖場(Udine，Italy)之雄性Sprague Dowley大鼠(220至240g)。每個籠子(26 x 41cm)住4隻大鼠。為適應環境，將籠子於測試前24小時置於實驗房間中。對動物餵食標準實驗室飲食及隨意飲取自來水且保持23±1℃之溫度及12小時光/暗循環，上午7點開燈。
所使用之強制游泳測試與Porsolt描述者相同，針對大鼠改良。簡言之，大鼠被單獨地丟進保持在22至23℃之含水玻璃圓筒(高度：45cm，直徑：20cm)中且留置於其中6分鐘。水足夠深以避免大鼠接觸水箱底部。當大鼠以直立位置浮在水中且只做出小動作以保持頭部於水面上時被判定為不動。活動性之持續時間在6分鐘之測試的後4分鐘期間被記錄下。活動性時間之持續時間之增加指示類似抗抑鬱劑之效應。
本發明之範圍中執行的測試蘊含在單次投與30分鐘後之劑量反應評估(急性)及一天提供兩次持續10天之一慢性劑量(即在急性投與後具有最佳效果之劑量)之效果評估。
所測量之端點為活動性時間(即大鼠在游泳上所花時間)：時間越長，抗抑鬱劑效果越好。
在急性及慢性測試中迪米拉西坦以及對照化合物之結果展示於表2及圖式1與2中：
在此測試中，亦由圖式1與2說明，迪米拉西坦係唯一表現出統計上顯著之抗抑鬱劑活性之西坦族，雖然不如阿密曲替林強效。
在第二慢性測試中，圖3中所說明，僅檢查媒劑及迪米拉西坦(100mg/kg p.o.)。所測得之平均活動性時間針對媒劑為53s而針對迪米拉西坦測試之大鼠為102s。
不同投與途徑之適宜性展示於圖式4中。雖然ip.途徑更有效，但
是p.o.途徑亦提供顯著結果。
奧拉西坦、左以拉西坦及普拉西坦被選為參考化合物，因為它們在WO 2007/104035中被提到且已知為比吡拉西坦更高效之益智劑(奧拉西坦效力高出2至4倍而普拉西坦效力高出8至30倍(參見http：//en.wikipedia.org/wiki/Racetam))且左以拉西坦一直被使用，除了吡拉西坦以外，其係唯一市售且作為抗驚厥劑在全世界廣泛使用之西坦族。
雖然本文展示及描述了本發明之目前較佳實施例，但應清楚地理解本發明並非局限此而可在以下申請專利範圍之範疇內以其他方式進行不同地實施及實踐。
Claims (14)
- 一種迪米拉西坦(Dimiracetam)或其溶劑化物之用途，其用於製造用於治療及/或預防抑鬱症之藥物。
- 如請求項1之迪米拉西坦或其溶劑化物之用途，其中迪米拉西坦係呈(S)及(R)對映異構體混合物之形式。
- 如請求項1之迪米拉西坦或其溶劑化物之用途，其中迪米拉西坦係呈單離之(S)或(R)對映異構體之形式。
- 如請求項1至3中任一項之迪米拉西坦或其溶劑化物之用途，其係投與：每日約1至約80mg/kg，較佳地約5至約65mg/kg，尤其約8至約50mg/kg之口服劑量，或每日約4至約25mg/kg，尤其從約8至約20mg/kg之肌肉內劑量或每日約1至約20mg/kg，尤其4至15mg/kg之靜脈內劑量或每日約8至約70mg/kg，較佳地10至65mg/kg，尤其15至35mg/kg之直腸劑量。
- 如請求項1至3中任一項之迪米拉西坦或其溶劑化物之用途，其每日劑量可以誘導100至500微莫耳濃度之血液含量。
- 如請求項1至3中任一項之迪米拉西坦或其溶劑化物之用途，其藥物形式適於按每Kg投與迪米拉西坦之以下每日劑量：口服：約1至約80mg/kg，較佳地約5至約65mg/kg，尤其約8至約20mg/kg，或經肌肉內：約4至約25mg/kg，尤其從約8至約20mg/kg，或經靜脈內：約1至約20mg/kg，尤其4至15mg/kg，或經直腸：約8至約70mg/kg，較佳地10至65mg/kg，尤其15至 35mg/kg。
- 如請求項1至3中任一項之迪米拉西坦或其溶劑化物之用途，其與選自以下組成之群之至少一種其他化合物組合使用：(i)抗抑鬱劑，(ii)非典型抗精神病藥，(iii)抗精神病藥，(iv)抗焦慮藥，(v)抗驚厥劑，(vi)用於阿茲海默氏(Alzheimer's)病治療之藥物，(vii)用於帕金森氏(Parkinson's)病治療之藥物，及(viii)用於偏頭痛治療之藥物，其中迪米拉西坦及至少一種其他化合物之投與可為合併、同時、依序地或分開投與。
- 如請求項4之迪米拉西坦或其溶劑化物之用途，其與選自以下組成之群之至少一種其他化合物組合使用：(i)抗抑鬱劑，(ii)非典型抗精神病藥，(iii)抗精神病藥，(iv)抗焦慮藥，(v)抗驚厥劑，(vi)用於阿茲海默氏病治療之藥物，(vii)用於帕金森氏病治療之藥物，及(viii)用於偏頭痛治療之藥物，其中迪米拉西坦及至少一種其他化合物之投與可為合併、同時、依序或分開投與。
- 如請求項5之迪米拉西坦或其溶劑化物之用途，其與選自以下組 成之群之至少一種其他化合物組合使用：(i)抗抑鬱劑，(ii)非典型抗精神病藥，(iii)抗精神病藥，(iv)抗焦慮藥，(v)抗驚厥劑，(vi)用於阿茲海默氏病治療之藥物，(vii)用於帕金森氏病治療之藥物，及(viii)用於偏頭痛治療之藥物，其中迪米拉西坦及至少一種其他化合物之投與可為合併、同時、依序或分開投與。
- 如請求項6之迪米拉西坦或其溶劑化物之用途，其與選自以下組成之群之至少一種其他化合物組合使用：(i)抗抑鬱劑，(ii)非典型抗精神病藥，(iii)抗精神病藥，(iv)抗焦慮藥，(v)抗驚厥劑，(vi)用於阿茲海默氏病治療之藥物，(vii)用於帕金森氏病治療之藥物，及(viii)用於偏頭痛治療之藥物，其中迪米拉西坦及至少一種化合物之投與可為合併、同時、依序或分開投與。
- 一種醫藥組合物，其包含迪米拉西坦及至少一種醫藥上可接受之媒劑、佐劑、載劑或稀釋劑。
- 如請求項11之醫藥組合物，其中迪米拉西坦之含量係供每日投 與如下劑量：口服組合物之情況下，50至4000mg，較佳地250至3200mg，更佳地400至2500mg；經肌肉內組合物之情況下，200至1200mg，較佳地400至1000mg；經靜脈內組合物之情況下，50至1000mg，較佳地200至800mg；或經直腸組合物(栓劑)之情況下，400至3500mg，較佳地至多3200mg且更佳地800至1600mg。
- 如請求項11之醫藥組合物，其包含選自以下組成之群之至少一種其他化合物：(i)抗抑鬱劑，(ii)非典型抗精神病藥，(iii)抗精神病藥，(iv)抗焦慮藥，(v)抗驚厥劑，(vi)用於阿茲海默氏病治療之藥物，(vii)用於帕金森氏病治療之藥物，且(viii)用於偏頭痛之藥物
- 一種製造物品，其包含如請求項11至13中任一項之醫藥組合物、容器或包裝及書面說明及投藥指示，諸如包裝插頁。
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