TWI730939B - 用於幫助睡眠之組成物及方法 - Google Patents
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- TWI730939B TWI730939B TW104104091A TW104104091A TWI730939B TW I730939 B TWI730939 B TW I730939B TW 104104091 A TW104104091 A TW 104104091A TW 104104091 A TW104104091 A TW 104104091A TW I730939 B TWI730939 B TW I730939B
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Abstract
一種用於在一個體中治療被干擾的睡眠或失眠的經控制的釋放配方被描述。該配方被配方以在複數個階段依序釋放一化合物或化合物的組合。
Description
本件申請案主張於2014年2月6日提申的美國臨時專利申請案第61/936,566號的優先權,它的全部內容在此被併入本案以作為參考資料。
本發明係有關於用於幫助睡眠之組成物及方法。
在蒙受睡眠中斷(sleep disruptions)的病患中,吾人可觀察到一在入睡的能力與維持睡著足夠久以感到休息的能力之間的明顯區別。用於失眠(insomnia)的藥物治療典型地聚焦在使一病患入睡。多數服用安眠藥(sleeping pills)的病患在半夜醒來而沒有完成8-小時睡眠週期。對於容許一病患入睡並且保持睡著歷時一足夠的時間週期的藥物有一需要。
下面描述一種經控制的釋放配方。該配方包括一或多個用於幫助睡眠的化合物,其中該配方被配方用於在
該配方被投藥給一個體之後在一特定時間和一特定劑量釋放各個化合物在該個體中。
在一具體例中,該配方被配方用於2至12個階段的釋放,其中在投藥該配方給一個體之後各個階段在一特定時間點開始釋放一化合物或化合物的一組合在該個體中。例如,在開始各個階段的釋放之間的時間間隔可以是0.5至23小時。該第一階段可以是用於立即釋放一化合物或化合物的組合。
該化合物或化合物們可被選自於由下列所構成的群組:巴比妥酸鹽類(barbiturates){例如,異戊巴比妥(amobarbital)[安密妥(Amytal)]、戊巴比妥(pentobarbital)[寧必妥(Nembutal)]、司可巴比妥(secobarbital)[速可眠(Seconal)]和苯巴比妥(phenobarbital)[魯米那(Luminal)];苯二氮平類(benzodiazepines){例如,可那氮平(clonazepam)[克諾平(Klonopin)北美;利福全(Rivotril)歐洲、亞洲]、二氮平(diazepam)[煩寧(Valium)]、艾司唑崙(estazolam)[悠樂丁(Prosom)]、氟硝西泮(flunitrazepam)[羅眠樂(Rohypnol)]、勞拉西泮(lorazepam)[安定文(Ativan)]、咪達唑崙(midazolam)[速眠安(Versed)]、硝西泮(nitrazepam)[眠確當(Mogadon)]、奧沙西泮(oxazepam)[舒寧(Serax)]、三唑崙(triazolam)[酣樂欣(Halcion)]、替馬西泮(temazepam)[Restoril、羥基安定(Normison)、Planum、鐵諾克斯(Tenox)和替馬安定(Temaze)]、氯氮卓(chlordiazepoxide)[利眠寧(Librium)]和阿普唑崙
(alprazolam)[贊安諾(Xanax)]};非-苯二氮平類(non-benzodiazepine)“Z-藥物(Z-drugs)”鎮靜劑(sedatives){例如,右佐匹克隆(eszopiclone)[魯尼斯塔(Lunesta)]、扎來普隆(zaleplon)[讚您眠(Sonata)]、佐沛眠(zolpidem)[安必恩(Ambien)]和佐匹克隆(zopiclone)[宜眠安(Imovane)、憶夢返(Zimovane)]};抗組織胺(antihistamines)[例如,二苯安明(diphenhydramine)、茶苯海明(dimenhydrinate)、杜亞拉明(doxylamine)、米氮平(mirtazapine)和普敏太定(promethazine)];植物組分或萃取物{來自,例如,Duboisia hopwoodii、洋甘菊(chamomile)、Prostanthera striatiflora、貓薄荷(catnip)、卡瓦胡椒(kava)[爪哇胡椒(Piper methysticum)]、纈草(valerian)、大麻屬(cannabis)和西番蓮屬(passiflora)[例如,野西番蓮(Passiflora incarnata)]};伐力多(Validol);水合氯醛(chloral hydrate);曲唑酮(trazodone);鴉片類(opiates)和類鴉片(opioids);蘇沃雷生(Suvorexant)(MK-4305,Merck & Co.);格魯米特(glutethimide);以及γ-羥基丁酸(γ-hydroxybutyric acid)。
在一具體例中,該配方是一用於口服投藥的錠劑或膠囊。該錠劑或膠囊可含有複數個顆粒,各個顆粒包括一藥物核心(drug core)和一囊封該核心的聚合物組成物(polymeric composition),其中該藥物核心含有該一或多個用於幫助睡眠的化合物。
亦描述一種在一個體中治療被干擾的睡眠(disturbed sleep)或失眠的方法。該方法包括投藥上面所描
述的配方給一需要它的個體。
一或多個具體例的詳細說明被提出在下面的說明。該等具體例的其他特徵、標的和優點從說明和申請專利範圍將是顯而易見的。
意外地發現:依序地投藥某些藥物或藥物的組合可在具有被干擾的睡眠或失眠的病患中誘發和維持睡眠這兩者。這個方法延長睡眠時間同時利用低於該等藥物的建議劑量,這降低成癮和其他副作用[例如,次晨損傷(next-morning impairment)]的風險。
如此處所用的,術語“被干擾的睡眠”、“睡眠干擾(sleep disturbances)”或“睡眠中斷(sleep disruption)”意指一特徵在於醒來感覺未恢復、在半夜醒來、在醒來後難以回復睡眠、入睡困難和/或太早清醒的情況。壓力、一健康狀況、疼痛、一醫藥品、時差和噪音是一些可導致被干擾的睡眠的因素。被干擾的睡眠在持續時間上可以是急性(亦即,短期)或慢性。
儘管對於睡眠具有充足的機會和環境,一具有失眠的個體經歷頻繁和長期被干擾的睡眠與日間損傷或困擾。
被干擾的睡眠可具有各種不同的負面結果,諸如疲勞、缺乏能量、主動性降低、白天嗜睡、緊張性頭痛、胃腸道症狀、煩躁、焦慮、情緒障礙、降低積極性以及在認知功能(注意力、集中和記憶)的損傷。
一個體是否具有被干擾的睡眠或失眠可藉由一在本技藝的熟練醫生所測定。
一種含有一或多個用於幫助睡眠的化合物或組成物[例如,鎮靜劑或安眠劑(hypnotic agents)]的經控制的釋放配方在此被描述。
此等用於幫助睡眠的化合物或組成物包括,但不限於,巴比妥酸鹽類[例如,異戊巴比妥(安密妥)、戊巴比妥(寧必妥)、司可巴比妥(速可眠)和苯巴比妥(魯米那);苯二氮平類{例如,可那氮平[克諾平(北美);利福全(歐洲、亞洲)]、二氮平(煩寧)、艾司唑崙(悠樂丁)、氟硝西泮(羅眠樂)、勞拉西泮(安定文)、咪達唑崙(速眠安)、硝西泮(眠確當)、奧沙西泮(舒寧)、三唑崙(酣樂欣)、替馬西泮(Restoril、羥基安定、Planum、鐵諾克斯和替馬安定)、氯氮卓(利眠寧)和阿普唑崙(贊安諾)};非-苯二氮平類“Z-藥物”鎮靜劑[例如,右佐匹克隆(魯尼斯塔)、扎來普隆(讚您眠)、佐沛眠(安必恩)和佐匹克隆(宜眠安、憶夢返)];抗組織胺(例如,二苯安明、茶苯海明、杜亞拉明、米氮平和普敏太定);植物組分或萃取物[例如,來自Duboisia hopwoodii、洋甘菊、Prostanthera striatiflora、貓薄荷、卡瓦胡椒(爪哇胡椒)、纈草、大麻屬
和西番蓮屬(例如,野西番蓮)的組分或萃取物];伐力多;水合氯醛;曲唑酮;鴉片類和類鴉片;蘇沃雷生(MK-4305,Merck & Co.);格魯米特;以及γ-羥基丁酸。標靶神經傳導物質受體(neurotransmitter receptors)[例如,組織胺(histamine)、GABA和食慾激素受體(orexin receptors)]的其他鎮靜劑或安眠劑亦可被使用在該配方。
在一具體例中,該經控制的釋放配方被配方以釋放一用於幫助睡眠的化合物/組成物或化合物/組成物的一組合。該配方在複數個階段(例如,2至12個階段)釋放該化合物/組成物或化合物/組成物的組合。各個階段在投藥該配方之後在一特定時間開始釋放該化合物/組成物或化合物/組成物的組合。
例如,該配方可立即地釋放一第一劑量的一化合物,在釋放該第一劑量之後1小時釋放一第二劑量的相同化合物,以及接著在釋放該第二劑量之後2小時釋放一第三劑量的該化合物。
在一具體例中,該經控制的釋放配方釋放二或更多用於幫助睡眠的化合物/組成物或化合物/組成物的組合。該配方在複數個階段(例如,2至12個階段)釋放該等化合物或組成物。各個階段在投藥該配方給一個體之後在一特定時間開始釋放一特定化合物/組成物或化合物/組成物的組合。
例如,該配方可立即地釋放一第一化合物,在釋放該第一化合物之後30分鐘釋放一第二化合物,以及接著
在釋放該第二化合物之後3.5小時一起釋放一第三化合物和一第四化合物。在另一個實例中,該配方可釋放一第一化合物在時間0、2小時、4小時和6小時以及一第二化合物在時間1小時、3小時、5小時和7小時。
在開始各個階段的釋放之間的時間間隔可以是30分鐘至23小時(例如,30分鐘、1小時、1.5小時、2小時、3小時、3.5小時、4小時、4.5小時、5小時、5.5小時、6小時、6.5小時、7小時、8小時、9小時、10小時、12.5小時、13小時、15小時、20小時、22小時,以及23小時)。各個階段可釋放一劑量的一化合物在0.01mg至100mg的範圍(例如,0.01mg、0.05mg、0.1mg、0.25mg、0.5mg、1mg、2mg,3mg、4mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg,以及100mg)。
該第一階段的釋放可以是一立即釋放,其中釋放一或多個活性試劑是在投藥該配方之後不久(例如,在30分鐘內)被開始。該第一階段的釋放亦可是一被延遲的釋放。
上面所描述的經控制的釋放配方可以是一錠劑[例如,一丸劑(pill)]或一膠囊[例如,一硬殼膠囊(hard-shelled capsule)或一軟凝膠(softgel)]用於口服投藥。其它配方[諸如植入物(implants)和貼片(patches)]亦可被使用。
用於配方和製造經控制的釋放配方的方法在本
技藝被知曉。參見,例如,Hong Wen and Kinam Park,2010,Oral Controlled Release Formulation Design and Drug Delivery:Theory to Practice,John Wiley & Sons,Inc。例如,經控制的釋放配方可根據特別的物理機制[例如,溶解(dissolution)、擴散(diffusion)、滲透(osmosis)和離子交換(ion exchange)]而被設計。
在一溶解系統中,一藥物被包圍或分佈在一聚合物組成物[例如,一聚合物膜(polymeric membrane)或一聚合物基質(polymeric matrix)]。當該聚合物組成物溶解時該藥物被釋放。該聚合物組成物的性質(例如,厚度和溶解率)決定藥物釋放。在一擴散系統中,該活性成分為了被釋放必須經由一聚合物組成物(例如,一聚合物膜或一聚合物基質)擴散。在一滲透為基礎的配方中,該藥物藉由一膨脹並且從滲透壓噴出藉此釋放該藥物的聚合物包衣(polymeric coating)而被囊封。離子交換配方依賴附接藥物分子至離子基團。該等藥物分子接著由其它離子所取代並且被釋放。在此所描述的經控制的釋放配方可利用一釋放機制或釋放機制的一組合。
在一具體例中,上面所描述的經控制的釋放配方可以是一具有複數個核心或層的錠劑。例如,該用於各個階段的釋放的藥物或藥物的組合可藉由聚合物層而被圍繞。該藥物或藥物的組合被釋放當該層溶解。
在一具體例中,一多顆粒系統(multiparticulate system)被採用。在這個系統中,該等活性化合物各個在複
數個顆粒[例如,在尺寸上自0.05至3.00mm的範圍的小珠粒(small beads)或微球體(microspheres]中被遞送,各個顆粒展現出所欲的特性(例如,釋放時間和速率)。例如,上面所描述的經控制的釋放配方可包括複數個顆粒。各個顆粒含有一包括一用於幫助睡眠的化合物或化合物的組合的核心以及一囊封該核心的經控制釋放的聚合物組成物(含有一或多個聚合物)。在各個顆粒中的該經控制釋放的聚合物組成物的性質決定各個顆粒的藥物釋放圖譜。該配方可包括未被包衣的顆粒用於立即釋放一藥物。任何上面所描述的或其他釋放機制(例如,溶解、擴散和滲透)可被採用在一多顆粒系統。該等複數個顆粒可被囊封在一膠囊或者被壓縮成一錠劑用於口服投藥。例如,一種三-階段釋放配方可含有3個類型的顆粒,各個類型用於各個階段的釋放。各個劑量的一用於各個階段的釋放的藥物藉由複數個顆粒被遞送。
用於經控制的釋放配方的天然和合成的聚合物在本技藝被知曉。此等聚合物包括,但不限於,蛋白質、多醣、核苷酸、褐藻酸(alginate)、幾丁聚醣(chitosan)、肝素(heparin)、三仙膠(xanthan gum)、澱粉、果膠(pectin)、明膠(gelatin)、κ/τ-鹿角菜膠(κ/τ-carrageenan)、羥丙基甲基纖維素(hydroxypropylmethylcellulose)、羥丙基纖維素(hydroxypropylcellulose)、羥乙基纖維素(hydroxyethylcellulose)、乙基纖維素(ethycellulose)、甲基纖維素(methylcellulose)、聚乙烯醇(polyvinyl alcohol)、聚丙烯酸(polyacrylic acid)、聚氧化乙烯(polyethylene oxide)、
泊洛沙姆(poloxamers)、普朗尼克(pluronics)、聚甲基丙烯酸酯(polymethacrylate)、纖維素(cellulose)、膠原蛋白(collagen)、尼龍(nylon)、聚氰基丙烯酸烷酯(polyalkylcyanoacrylate)、聚乙烯(polyethylene)、聚乙烯-共-乙酸乙烯酯(polyethylene-co-vinylacetate)、聚甲基丙烯酸羥乙酯(polyhydroxythyl methacrylate)、聚甲基丙烯酸羥丙乙酯(polyhydroxypropylethyl methacrylate)、聚甲基丙烯酸甲酯(polymethyl methacrylate)、聚胺甲酸酯(polyurethane)以及矽(silicon)。用於藥學應用的商業上可獲得的聚合物包括EUDRAGIT®聚甲基丙烯酸酯。
在一具體例中,該經控制的釋放配方採用一腸包衣(enteric coating)或其他用於延遲藥物釋放直到該藥物到達小腸或結腸的包衣。以這個方式延遲藥物釋放亦將控制藥物釋放時間。此等包衣在本技藝被知曉。
當一化合物或組成物被釋放時,它變成對身體可利用的。各個階段的釋放可具有特定的釋放速率。例如,一階段可具有一脈動-釋放圖譜(pulsatile-release profile),其中一藥物在一無釋放的期間之後被快速地和完全地釋放。一階段亦可具有一個一階釋放速率(first-order release rate),其中一藥物在一遞減的釋放速率被釋放。一個零階釋放速率(zero-order release rate)(亦即,一恆定的釋放速率)亦可被採用。一整個劑量(或者它的一顯著部分)的一化合物可被釋放在一短期間內或在一延長的期間。例如,該配方可被設計以釋放至少50%(例如,超過60%、70%、75%、80%、85%、
90%,或95%)的一劑量的一化合物在開始釋放的30分鐘內。
該經控制的釋放配方亦可包括一或多個藥學賦形劑(pharmaceutical excipients),例如,黏合劑(binders)、塑化劑(plasticizers)、潤滑劑(lubricants)、稀釋劑(diluents)、填充劑(fillers)、著色劑(coloring agents)、調味劑(flavoring agents)、滑動劑(glidants)和防腐劑(preservatives)。
該經控制的釋放配方可每天或如需要的話被投藥給一病患以誘發或維持睡眠。
下面的特定實施例僅被解釋為例示說明,並且絲毫不以任何方式限制本揭示的剩餘部分。沒有進一步詳盡闡述,被相信的是:一熟習此技藝者可根據在此的描述,利用本揭示至它的最大程度。在此所引述的所有刊物藉此以它們的整體被併入本案以做為參考資料。
一配方(呈錠劑或膠囊形式)釋放藥物在3個階段。在該第一階段,釋放50mg的苯海拉明(Benadryl)在攝取之後立即地開始。在該第二階段,釋放5mg的安必恩在開始釋放苯海拉明之後2-3小時開始。在該第二階段開始之後2-3小時,釋放0.5mg的安定文被開始。
一配方(呈錠劑或膠囊形式)被配方以在攝取之後開始立即釋放50mg的苯海拉明、10mg的褪黑激素(melatonin)和25mg的茶胺酸(Theanine)。在2小時之後,釋放5mg的安必恩被開始。在開始釋放安必恩之後3小時,釋放0.5mg的安定文和1mg
的贊安諾被開始。
用於釋放二苯安明HCl(diphenhydramine HCl){亦即,2-(二苯基甲氧基)-N,N-二甲基乙胺[2-(diphenylmethoxy)-N,N-dimethylethanamine]}、酒石酸佐沛眠(zolpidem tartrate){亦即,N,N-二甲基-2-(6-甲基-2-p-甲苯基咪唑并[1,2-a]吡啶-3-基)乙醯胺[N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acet amide]}和勞拉西泮{亦即,(RS)-7-氯-5-(2-氯苯基)-3-羥基-1,3-二氫-2H-1,4-苯並二氮平-2-酮[(RS)-7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one]}的硬明膠膠囊被製備。
該等膠囊被設計以經由pH-依賴的包衣呈一階段化的順序控制釋放該等3種藥物:未被包衣的放二苯安明HCl用於立即釋放,被包衣的佐沛眠用於在投藥之後大約2小時釋放,以及被包衣的勞拉西泮用於在投藥之後大約4小時釋放。
各個膠囊含有下列試劑:(1)50mg的未被包衣的二苯安明HCl;(2)5mg的被包衣以EUDRAGIT® L30 D-55[在pH 5.5以上溶解(具有一半-最大藥物釋放在pH 5.8以及最大釋放在pH 6.3)]呈多顆粒形式的酒石酸佐沛眠;以及(3)0.5mg的被包衣以EUDRAGIT® L/S 12,5(1:1)[在pH 6.5以上溶解(具有一半-最大藥物釋放在pH 7.2)]呈多顆粒形式的勞拉西泮。該等包衣被選擇以達到釋放酒石酸佐沛眠與胃排空以及釋放勞拉西泮當該藥物到達
腸。
6種膠囊在燒杯中被個別地試驗各個活性試劑的pH-依賴釋放。如在表1所顯示的,在pH 2,超過89%的二苯安明HCl在30分鐘內被釋放,而沒有酒石酸佐沛眠或勞拉西泮被釋放。在pH 6.4,超過71%的酒石酸佐沛眠(但是沒有勞拉西泮)在30分鐘內被釋放。在pH 7.2,超過70%的勞拉西泮在30分鐘內被釋放。
在上面實施例3所描述的膠囊在科羅拉多州柯林斯堡的CARE研究中被試驗在狗。狗的睡眠模式是多相的。
睡眠的各個回合在自數分鐘至大約45分鐘的範圍。狗跟隨晝夜節律(circadian rhythm)。牠們在白天的期間不時入睡,但是在夜間獲得多數牠們所需的睡眠。
在第1天,4隻正常、未被處理的比格犬(Beagle dogs)被個別地安置並且藉由被安裝在上面的錄影-攝影機連續地監測歷時24小時。
在第3天,各個狗在早晨被口服地餵食以一膠囊、被個別地安置在如在第1天的相同房間,以及藉由被安裝在上面的錄影-攝影機連續地監測歷時24小時。
在第1天和第3天自中午12點至晚上8點所記錄的錄影被分析。由各個狗的各個睡眠回合的時間被測量以及在8小時的過程中各個狗的總睡眠時間被計算。下面的表2概述試驗結果。
如在表2所顯示的,該等膠囊在所有4隻被處理的比格犬中在總睡眠時間上導致一顯著的增加。
關於人類研究,相同於在實施例3所描述的那些的硬明膠膠囊被製備,除了勞拉西泮被包衣以EUDRAGIT® L 12,5取代EUDRAGIT® L/S 12,5(1:1)以說明在狗與人類的胃腸pH之間的輕微差異。EUDRAGIT® L 12,5在pH 6.0以上溶解。
被預期的是:在投藥該等膠囊給人類個體之後,二苯安明將被立即地釋放並且是有效的歷時上達4小時。佐沛眠將在投藥之後大約2小時被釋放並且大約2小時之後達到它的tmax(亦即,在血漿中最大濃度的時間)。勞拉西泮將在投藥該等膠囊之後大約4小時被釋放並且在投藥之後大約6小時達到它的tmax。
在這個說明書所揭示的所有特徵可呈任何組合
而被組合。被揭示在這個說明書的各個特徵可由一作為相同、等效或相似目的的另擇特徵所代替。因此,除非另有明確地說明,被揭示的各個特徵僅是一系列的等效或相似特徵的一實例。
從上面的描述,一熟習此技藝者可容易地確定所描述的具體例的必要特徵,並且沒有背離其精神和範疇,可做出具體例的各種不同的變化和修飾以使它適應各種不同的用途和情況。因此,其他具體例亦在申請專利範圍內。
Claims (13)
- 一種經控制釋放的組成物,其被調配以用於在一第一階段立即釋放二苯安明HCl(diphenhydramine HCl)、在該第一階段開始之後2-3小時開始的一第二階段釋放酒石酸佐沛眠(zolpidem tartrate)、以及在該第二階段開始之後2-3小時開始的一第三階段釋放勞拉西泮(lorazepam)。
- 如請求項1的組成物,其中該組成物是一用於口服投藥的錠劑或膠囊。
- 如請求項2的組成物,其中該錠劑是一多層的或多核心的錠劑。
- 如請求項2的組成物,其中該錠劑或膠囊含有複數個顆粒,各個顆粒包括一藥物核心和一囊封該核心的聚合物組成物,其中該藥物核心含有一或多個用於幫助睡眠的化合物。
- 如請求項1的組成物,其中該組成物含有50mg的二苯安明HCl、5mg的酒石酸佐沛眠、以及0.5mg的勞拉西泮。
- 如請求項5的組成物,其中該組成物是一用於口服投藥的錠劑或膠囊。
- 如請求項6的組成物,其中該錠劑或膠囊含有複數個顆粒,各個顆粒包括一藥物核心和一囊封該核心的聚合物組成物,其中該藥物核心含有酒石酸佐沛眠或勞拉西泮。
- 如請求項7的組成物,其中該聚合物組成物包括聚甲基丙烯酸酯(polymethacrylate)。
- 如請求項1的組成物,其中該組成物含有二苯安明HCl、酒石酸佐沛眠和勞拉西泮作為僅有的3種活性化合物。
- 一種如請求項1的組成物於製造一藥物的用途,該藥物係用於治療一個體之受干擾的睡眠或失眠。
- 如請求項7的組成物,其中該含有酒石酸佐沛眠的藥物核心藉由一第一聚合物組成物而被囊封,以及該含有勞拉西泮的藥物核心藉由一第二聚合物組成物而被囊封,該第一聚合物組成物具有在5.5以上的溶解pH,以及該第二聚合物組成物具有在6或6.5以上的溶解pH。
- 一種經控制釋放的組成物,包含(i)未被包衣的二苯安明HCl,(ii)被一第一聚合物組成物包衣的酒石酸佐沛眠;以及(iii)被一第二聚合物組成物包衣的勞拉西泮;該第一聚合物組成物具有在5.5以上的溶解pH,以及該第二聚合物組成物具有在6或6.5以上的溶解pH。
- 一種如請求項12的組成物於製備一藥物的用途,該藥物係用於治療一個體之受干擾的睡眠或失眠。
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US10398662B1 (en) | 2015-02-18 | 2019-09-03 | Jazz Pharma Ireland Limited | GHB formulation and method for its manufacture |
AU2017260019A1 (en) * | 2016-05-06 | 2018-11-22 | Sociétés des Produits Nestlé S.A. | Valerian composition and related methods |
US11504347B1 (en) | 2016-07-22 | 2022-11-22 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11602513B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11986451B1 (en) | 2016-07-22 | 2024-05-21 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
UY37341A (es) | 2016-07-22 | 2017-11-30 | Flamel Ireland Ltd | Formulaciones de gamma-hidroxibutirato de liberación modificada con farmacocinética mejorada |
US11602512B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US20180263936A1 (en) | 2017-03-17 | 2018-09-20 | Jazz Pharmaceuticals Ireland Limited | Gamma-hydroxybutyrate compositions and their use for the treatment of disorders |
AU2018448857A1 (en) * | 2018-11-06 | 2021-06-03 | Lan Bo Chen | Composition and method for aiding sleep |
WO2020106735A1 (en) | 2018-11-19 | 2020-05-28 | Jazz Pharmaceuticals Ireland Limited | Alcohol-resistant drug formulations |
WO2020178695A1 (en) | 2019-03-01 | 2020-09-10 | Flamel Ireland Limited | Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state |
CN110075302A (zh) * | 2019-04-19 | 2019-08-02 | 陶燃 | 一种治疗抑郁和失眠的组合物及其用途 |
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