JP2022539944A - Novel pharmaceutical compositions and methods for treating psychiatric, behavioral and cognitive disorders - Google Patents
Novel pharmaceutical compositions and methods for treating psychiatric, behavioral and cognitive disorders Download PDFInfo
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- JP2022539944A JP2022539944A JP2021566489A JP2021566489A JP2022539944A JP 2022539944 A JP2022539944 A JP 2022539944A JP 2021566489 A JP2021566489 A JP 2021566489A JP 2021566489 A JP2021566489 A JP 2021566489A JP 2022539944 A JP2022539944 A JP 2022539944A
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- azelastine
- pharmaceutically acceptable
- pharmaceutical composition
- acceptable salt
- donepezil
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Abstract
アゼラスチン又はアゼラスチンの薬学的に許容される塩及びドネペジル又はリバスチグミン又はガランタミン又はその薬学的に許容される塩の治療活性成分を含有する医薬組成物が、開示される。精神、行動、認知障害に罹患している患者を治療するために医薬組成物を使用するための方法もまた、開示される。Pharmaceutical compositions containing azelastine or a pharmaceutically acceptable salt of azelastine and the therapeutically active ingredients of donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof are disclosed. Also disclosed are methods for using the pharmaceutical compositions to treat patients suffering from mental, behavioral, or cognitive disorders.
Description
発明の分野
[001] 本発明は、臨床医学の分野、すなわち、中枢神経系に対する、原因を様々とする本質的な損傷といった症例において、精神、行動、認知障害の発現を緩和する、向神経性作用を示す医薬組成物の使用の組み合わせに関する。
Field of Invention
[001] The present invention demonstrates neurotropic action in the field of clinical medicine, i.e., in cases of intrinsic damage of various causes to the central nervous system, which alleviates the manifestation of mental, behavioral, and cognitive deficits. It relates to the combination of uses of the pharmaceutical composition.
発明の背景
[002] アルツハイマー病（ＡＤ）は通常、ゆっくりと始まり長い期間をかけて次第に悪化する、進行性で慢性的な神経変性疾患である。アルツハイマー病は、高齢者の間では認知症の最も一般的な原因である。認知症は、人の日常生活及び活動を妨げる程度まで、認知機能－思考、記憶、及び推論－並びに行動能力が失われる。初期では記憶喪失は軽度であるが、末期のＡＤでは、人は会話を続けたり、周囲の状況に反応したりする能力を失っている。治療しなければ、ＡＤは最終的に死に至る。進行の速度は変動することがあるが、診断後の典型的な平均余命は３～９年である。
Background of the invention
[002] Alzheimer's disease (AD) is a progressive, chronic, neurodegenerative disease that usually begins slowly and worsens over time. Alzheimer's disease is the most common cause of dementia among the elderly. Dementia is the loss of cognitive functions—thinking, memory, and reasoning—and behavioral abilities to the extent that they interfere with a person's daily life and activities. Although amnesia is mild in the early stages, in late-stage AD people lose the ability to hold a conversation or react to their surroundings. Without treatment, AD is ultimately fatal. The rate of progression can vary, but typical life expectancy after diagnosis is 3-9 years.
[003] ＡＤは、ニューロンの早すぎる死によって特徴づけられる多遺伝子性／多因子性の複雑な障害である。ＡＤの病因の第一動因（Primum Movens）として、アミロイド仮説が認識されているが、アミロイド前駆体タンパク質（ＡＰＰ）遺伝子及びプレセニリン（ＰＳ）遺伝子と関連する変異性の遺伝だけでは、老人斑及び血管（アミロイド血管症）におけるアミロイド沈着、タウタンパク質のリン酸化過剰による神経原線維変化（ＮＦＴ）形成、シナプス及び樹状突起の分枝の減少（desarborization）、並びにニューロンの消失によって代表される、ＡＤにおいて存在する神経病理学的所見を、完全には説明しない。これらの所見には、おそらくミトコンドリア機能不全と関連する神経炎症反応、酸化ストレス、及びフリーラジカル形成、興奮毒性反応、コレステロール代謝及び脂質ラフトにおける変化、神経伝達物質（とりわけアセチルコリン）及び神経栄養因子の働きの欠乏、ユビキチン－プロテアソームの不完全な活性、並びにシャペロン系及び脳血管調節の不全が伴う。これらの神経化学的現象はすべて、可能性として考えられる治療標的となるが、単一の薬剤だけで神経変性に関与する複雑なメカニズムを相殺することができる可能性は、非常に低い。 [003] AD is a complex polygenic/multifactorial disorder characterized by premature neuronal death. Although the amyloid hypothesis is recognized as the primary cause of AD pathogenesis, mutational inheritance alone associated with the amyloid precursor protein (APP) gene and the presenilin (PS) gene can lead to senile plaques and vascular disease. in AD, typified by amyloid deposition in (amyloid angiopathy), neurofibrillary tangle (NFT) formation due to hyperphosphorylation of tau protein, synaptic and dendritic desarborization, and loss of neurons It does not fully explain the neuropathological findings that are present. These findings include neuroinflammatory responses, oxidative stress, and free radical formation, possibly associated with mitochondrial dysfunction, excitotoxic responses, alterations in cholesterol metabolism and lipid rafts, neurotransmitter (especially acetylcholine) and neurotrophic factor activity. deficiency, defective activity of the ubiquitin-proteasome, and deficiencies in the chaperone system and cerebrovascular regulation. Although all of these neurochemical phenomena represent potential therapeutic targets, it is highly unlikely that a single agent alone can counteract the complex mechanisms involved in neurodegeneration.
[004] １９８０年代初期に、ＡＤ関連性の記憶障害は、前脳基底核中のニューロンの消失による、罹患者の脳におけるコリン作動性の欠損に一部起因すると考えられ、これはＡＤのコリン作動性仮説のもとになった。コリンドナー（前駆体）及びアセチルコリン自体は薬理学的取扱いが難しい物質であったので（すなわち、脳のコリン作動性神経伝達を増加させることには使えない）、また逆説的に、アセチルコリンエステラーゼ活性が認知機能悪化と並行してＡＤ脳において徐々に減少したことを考慮して、ＡＣｈＥＩが、シナプス前終末におけるアセチルコリン合成を増強するために、シナプス間隙においてアセチルコリン分解を阻害し、シナプス前部でのコリン再取込みを増加させ、これによりコリン作動性神経伝達を促進する選択肢として提唱された。この基準を満たす第１の候補はタクリン（テトラヒドロアミノアクリジン）であり、これは、１９９３年に市場に出た後、その肝毒性及び忍容性不良のために、すぐに人気がなくなった；３年後の１９９６年に、ドネペジルが、ＡＤの軽度～中等度の症例の治療用に、ＦＤＡによって承認された。他のＡＣｈＥＩ、リバスチグミン及びガランタミンは、数年後に導入された。 [004] In the early 1980s, AD-related memory deficits were thought to be due in part to cholinergic deficits in the brains of affected individuals, due to loss of neurons in the basal forebrain, which is associated with AD's cholinergic became the basis for the operative hypothesis. Choline donors (precursors) and acetylcholine themselves have been pharmacologically intractable substances (i.e., cannot be used to increase cholinergic neurotransmission in the brain), and paradoxically, acetylcholinesterase activity has Considering its gradual decline in AD brains paralleling cognitive deterioration, AChEI inhibited acetylcholine breakdown in the synaptic cleft to enhance acetylcholine synthesis at presynaptic terminals and choline at presynaptic sites. It has been proposed as an option to increase reuptake and thereby enhance cholinergic neurotransmission. The first candidate to meet this criterion is tacrine (tetrahydroaminoacridine), which quickly fell out of favor after it entered the market in 1993 due to its hepatotoxicity and poor tolerance;3 Years later, in 1996, donepezil was approved by the FDA for the treatment of mild to moderate cases of AD. Other AChEIs, rivastigmine and galantamine, were introduced years later.
[005] しかしながら、ドネペジル、リバスチグミン、及びガランタミンなどのアセチルコリンエステラーゼ阻害剤は、いつか将来にＡＤを回復させたり又はこれらの能力の喪失を予防したりするようなことはないであろう。したがってＡＤは、現在、治療法がなく、発明者らは、疾患を逆転させ、疾患が発症するのを遅延させ、及び予防するためのよりよい手段を見つけるために努力している。 [005] However, acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine are not likely to reverse AD or prevent loss of these abilities sometime in the future. AD therefore currently has no cure and the inventors are striving to find better means to reverse, delay the onset of, and prevent the disease.
[006] 一方、ＡＤと関連する遺伝的、細胞の、及び分子的変化は、免疫プロセス及び炎症プロセスの活性化が疾患の一部となっているという証拠を支持する。ＮＳＡＩＤの長期の使用の大きな利点もまた、疫学調査において示された。したがって、ＡＤが一部では炎症性疾患であり、炎症の阻害がＡＤを治療する選択肢であることが、一般に受け入れられている。 [006] On the other hand, the genetic, cellular and molecular alterations associated with AD support evidence that activation of immune and inflammatory processes is part of the disease. Greater benefits of long-term use of NSAIDs have also been demonstrated in epidemiological studies. Therefore, it is generally accepted that AD is in part an inflammatory disease and inhibition of inflammation is an option for treating AD.
[007] 炎症は、ＡＤ脳の病理学的に脆弱な領域において明らかに生じており、錯綜した局所的末梢炎症反応に関しても同じことが言える。末梢において、変性組織及び極めて不溶性の異常物質の沈着は、炎症の古典的な刺激物となっている。同様にＡＤ脳において、損傷を受けたニューロン及び神経突起、並びに極めて不溶性のアミロイドβペプチド沈着物、並びに神経原線維変化は、炎症を起こすような刺激を明らかに与える。これらの刺激が散在しており、微小局在しており、及びＡＤの発症前の初期から終末期まで存在するので、補体、サイトカイン、急性期反応物質、及び他の炎症性メディエーターの局所的なアップレギュレーションもまた、散在しており、微小局在しており、及び慢性的である。ＡＤの炎症メカニズムからの直接的な及び第三者による損傷が、長年にわたって蓄積し、そのもとになった非常に病原性のプロセスを著しく悪化させる可能性がある。このように、動物モデル及び臨床研究は、ＡＤの炎症がＡＤの病因にかなり寄与していることを、これまでのところ強く示唆している。ＡＤの炎症プロセス及び免疫調節プロセスをより理解することによって、この破壊的な障害の発症を逆転させるか、遅延させるか、又は予防し得る、抗炎症性のアプローチの開発が可能となるはずである。 [007] Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and the same is true for the convoluted local peripheral inflammatory response. In the periphery, degenerating tissue and deposits of highly insoluble abnormal substances have become classic stimuli of inflammation. Similarly, in AD brains, damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles clearly provide inflammatory stimuli. Because these stimuli are disseminated, microlocalized, and present early before the onset of AD until the end of life, the localization of complement, cytokines, acute phase reactants, and other inflammatory mediators The upregulation is also diffuse, microlocalized and chronic. Direct and third-party damage from the inflammatory mechanisms of AD can accumulate over many years and significantly exacerbate the underlying highly pathogenic process. Thus, animal models and clinical studies so far strongly suggest that AD inflammation contributes significantly to AD pathogenesis. A better understanding of the inflammatory and immunomodulatory processes of AD should enable the development of anti-inflammatory approaches that could reverse, delay or prevent the onset of this devastating disorder. .
[008] アゼラスチンは、薬理学的に第２の世代の抗ヒスタミン薬として分類され、Ｈ１受容体に対して比較的選択的で、非鎮静型の競合的拮抗薬である。さらに独特なことに、抗ヒスタミン性の効果及び肥満細胞安定化の効果に加え、アゼラスチンによる炎症性メディエーターの阻害は、アゼラスチンを二重に作用する抗炎症薬の新たな世代のひとつに位置づける。炎症及びアレルギーのいくつかの他のメディエーターを調整するアゼラスチンの能力は、アゼラスチンの作用のメカニズムに寄与する。インビトロ及びインビボにおける研究並びに臨床試験は、炎症性細胞の直接的な阻害及び安定化の二重の効果を支持する。インビトロにおけるデータは、肥満細胞脱顆粒の阻害に対するアゼラスチンの親和性がまた、とりわけ、ロイコトリエン及びインターロイキン－１βを含む他の炎症性メディエーターの放出をも減少させ得ることを示す。アゼラスチンはまた、腫瘍壊死因子－α、ロイコトリエン、エンドセリン－１、及び血小板活性化因子などの、炎症の他のメディエーターにも直接拮抗する。そのため、アゼラスチン並びにドネペジル及び／又はリバスチグミン及び／又はガランタミンの独特な組み合わせは、相乗効果を生む観点から、ＡＤの革新的で有望な治療となることが期待される。 [008] Azelastine is pharmacologically classified as a second generation antihistamine and is a non-sedating competitive antagonist that is relatively selective for H1 receptors. More uniquely, the inhibition of inflammatory mediators by azelastine, in addition to its antihistaminic and mast cell stabilizing effects, places azelastine in a new generation of dual-acting anti-inflammatory agents. Azelastine's ability to modulate several other mediators of inflammation and allergy contributes to azelastine's mechanism of action. In vitro and in vivo studies and clinical trials support a dual effect of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that azelastine's affinity for inhibition of mast cell degranulation can also reduce the release of other inflammatory mediators, including leukotrienes and interleukin-1β, among others. Azelastine also directly antagonizes other mediators of inflammation such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet activating factor. Therefore, the unique combination of azelastine and donepezil and/or rivastigmine and/or galantamine is expected to be an innovative and promising treatment for AD from a synergistic point of view.
発明の概要
[009] 本発明は、２つの活性成分及び１つ以上の薬学的に許容される賦形剤を含む医薬組成物を含む。この医薬組成物は、アゼラスチン又はアゼラスチンの薬学的に許容される塩である第１の活性成分、並びにドネペジル及び／又はリバスチグミン及び／又はガランタミン及び／又はその任意の薬学的に許容される塩である第２の活性成分を含む。
SUMMARY OF THE INVENTION
[009] The present invention includes pharmaceutical compositions comprising two active ingredients and one or more pharmaceutically acceptable excipients. The pharmaceutical composition is a first active ingredient that is azelastine or a pharmaceutically acceptable salt of azelastine, and donepezil and/or rivastigmine and/or galantamine and/or any pharmaceutically acceptable salt thereof It contains a second active ingredient.
[0010] アルツハイマー病、血管性認知症、パーキンソン病、ハンチントン病、又はその任意の組み合わせなどの、１つ以上の精神、行動、又は認知障害の治療のための、（ｉ）アゼラスチン又はアゼラスチンの薬学的に許容される塩、（ｉｉ）ドネペジル又はリバスチグミン又はガランタミン又はその薬学的に許容される塩又はその任意の組み合わせ、及び（ｉｉｉ）１つ以上の薬学的に許容される賦形剤を含む組成物の使用が、本発明の実施形態に含まれる。 [0010] (i) azelastine or the pharmacy of azelastine for the treatment of one or more mental, behavioral or cognitive disorders such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, or any combination thereof (ii) donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients. Use of objects is included in embodiments of the present invention.
[0011] アルツハイマー病、血管性認知症、パーキンソン病、ハンチントン病、又はその任意の組み合わせなどの、１つ以上の精神、行動、又は認知障害を治療するための医薬の製造のための、（ｉ）アゼラスチン又はアゼラスチンの薬学的に許容される塩、（ｉｉ）ドネペジル又はリバスチグミン又はガランタミン又はその薬学的に許容される塩又はその任意の組み合わせ、及び（ｉｉｉ）１つ以上の薬学的に許容される賦形剤を含む組成物の使用もまた、本発明の範囲内に含まれる。 (i ) azelastine or a pharmaceutically acceptable salt of azelastine, (ii) donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof or any combination thereof, and (iii) one or more pharmaceutically acceptable Also included within the scope of the invention is the use of compositions containing excipients.
[0013] 本発明のいくつかの実施形態では、医薬組成物中のアゼラスチンの薬学的に許容される塩は、アゼラスチン塩酸塩であり、この医薬組成物中のドネペジル又はリバスチグミン又はガランタミンの薬学的に許容される塩は、ドネペジル塩酸塩又はリバスチグミン酒石酸塩又はガランタミン臭化水素酸塩である。 [0013] In some embodiments of the present invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride, and the pharmaceutically acceptable salt of donepezil or rivastigmine or galantamine in the pharmaceutical composition. Acceptable salts are donepezil hydrochloride or rivastigmine tartrate or galantamine hydrobromide.
[0014] 本発明のいくつかの実施形態では、医薬組成物中のアゼラスチン塩酸塩（及び／又はその他の塩）は、約４ｍｇ～約２０ｍｇの量で提供され、ドネペジル塩酸塩（及び／又はその他の塩）は、約１ｍｇ～約４ｍｇの量で及び／又はリバスチグミン酒石酸塩（及び／又はその他の塩）は、約１ｍｇ～約２ｍｇの量で及び／又はガランタミン臭化水素酸塩（及び／又はその他の塩）は、約１ｍｇ～約３ｍｇの量で提供される。１日当たり約２０ｍｇ以下の量のアゼラスチン又はその塩（約１～２０ｍｇ又は２～１９ｍｇ又は３～１８ｍｇ又は４～１７ｍｇ又は５～１５ｍｇ又は６～１２ｍｇ又は８～１０ｍｇ又は３～１１ｍｇ又は２～１３ｍｇ又は７～１６ｍｇ等）並びに１日当たり約２３ｍｇ以下の量のドネペジル若しくはその塩（約１～２３ｍｇ若しくは２～２２ｍｇ若しくは３～２０ｍｇ若しくは４～１８ｍｇ若しくは５～１６ｍｇ若しくは６～１５ｍｇ若しくは７～１２ｍｇ若しくは１．５～３ｍｇ若しくは１～２ｍｇ若しくは２．５～５ｍｇ等）及び／又は１日当たり約９．５ｍｇ以下の量のリバスチグミン若しくはその塩の量（約１～９．５ｍｇ若しくは２～９ｍｇ若しくは３～８ｍｇ若しくは４～７ｍｇ若しくは５～６ｍｇ若しくは３．５～８．５ｍｇ若しくは２．５～７．５ｍｇ等）及び／又は１日当たり約２４ｍｇ以下の量のガランタミン若しくはその塩の量（約１～２４ｍｇ若しくは２～２２ｍｇ若しくは３～２０ｍｇ若しくは４～１８ｍｇ若しくは５～１６ｍｇ若しくは６～１５ｍｇ若しくは７～１２ｍｇ若しくは８～１０ｍｇ若しくは０．５～２ｍｇ若しくは０．８～２．８ｍｇ若しくは１～１．５ｍｇ若しくは１．２～２．５ｍｇ等）を送達するために製剤される組成物が、好ましい。用途に応じて、これらの任意の１つ以上を、ある特定の実施形態において、より多い量で使用することができる。 [0014] In some embodiments of the invention, azelastine hydrochloride (and/or other salt) in the pharmaceutical composition is provided in an amount of about 4 mg to about 20 mg, and donepezil hydrochloride (and/or other salt) is provided in an amount of about 4 mg to about 20 mg. salt) in an amount from about 1 mg to about 4 mg and/or rivastigmine tartrate (and/or other salts) in an amount from about 1 mg to about 2 mg and/or galantamine hydrobromide (and/or other salts) are provided in amounts of about 1 mg to about 3 mg. Azelastine or a salt thereof in an amount of about 20 mg or less per day (about 1-20 mg or 2-19 mg or 3-18 mg or 4-17 mg or 5-15 mg or 6-12 mg or 8-10 mg or 3-11 mg or 2-13 mg or 7-16 mg, etc.) and donepezil or a salt thereof in an amount up to about 23 mg per day (about 1-23 mg, or 2-22 mg, or 3-20 mg, or 4-18 mg, or 5-16 mg, or 6-15 mg, or 7-12 mg, or 1. 5-3 mg or 1-2 mg or 2.5-5 mg, etc.) and/or an amount of rivastigmine or its salt in an amount of about 9.5 mg or less per day (about 1-9.5 mg or 2-9 mg or 3-8 mg or 4 to 7 mg or 5 to 6 mg or 3.5 to 8.5 mg or 2.5 to 7.5 mg) and/or an amount of galantamine or its salt in an amount of about 24 mg or less per day (about 1 to 24 mg or 2 to 22 mg or 3-20 mg or 4-18 mg or 5-16 mg or 6-15 mg or 7-12 mg or 8-10 mg or 0.5-2 mg or 0.8-2.8 mg or 1-1.5 mg or 1.2- Compositions formulated to deliver 2.5 mg) are preferred. Any one or more of these may be used in higher amounts in certain embodiments, depending on the application.
[0015] 本発明はまた、固体形態又は液体形態である医薬組成物の経口医薬投薬形態をも含む。 [0015] The present invention also includes oral pharmaceutical dosage forms of the pharmaceutical composition in solid or liquid form.
[0016] 本発明は、さらに、アルツハイマー病、血管性認知症、又はパーキンソン病などの神経変性障害を有する患者への投薬形態の投与を通しての、医薬組成物の経口医薬投薬形態の医学的使用を含む。 [0016] The present invention further provides the medical use of an oral pharmaceutical dosage form of the pharmaceutical composition through administration of the dosage form to a patient having a neurodegenerative disorder such as Alzheimer's disease, vascular dementia, or Parkinson's disease. include.
[0017] 本発明のいくつかの実施形態では、約８ｍｇ～約１２ｍｇの量のアゼラスチン塩酸塩（及び／又はその他の塩）並びに約１ｍｇ～約４ｍｇの量のドネペジル塩酸塩又は約１ｍｇ～約２ｍｇの量のリバスチグミン酒石酸塩又は約１ｍｇ～約３ｍｇの量のガランタミン臭化水素酸塩を含有する医薬組成物の経口医薬投薬形態は、中期～末期アルツハイマー病を有する患者に投与される。実施形態において、組成物の構成成分のいずれかに関して本明細書において開示される範囲のいずれも、固体、液体、ゲル、又は溶液などの経口剤として製剤することができる。 [0017] In some embodiments of the invention, azelastine hydrochloride (and/or other salts) in an amount of about 8 mg to about 12 mg and donepezil hydrochloride in an amount of about 1 mg to about 4 mg or about 1 mg to about 2 mg. or galantamine hydrobromide in an amount of about 1 mg to about 3 mg is administered to a patient with intermediate to late stage Alzheimer's disease. In embodiments, any of the ranges disclosed herein for any of the components of the composition can be formulated as oral dosage forms such as solids, liquids, gels, or solutions.
発明の詳細な説明
[0018] 本発明の発明者らは、驚くべきことに、活性剤、アゼラスチンの塩形態及びドネペジル又はリバスチグミン又はガランタミンの塩形態を含む経口投薬形態を有する医薬組成物が、精神、行動、認知障害に罹患している患者を治療するのに適していることを見出した。
Detailed description of the invention
[0018] The inventors of the present invention have surprisingly found that a pharmaceutical composition having an oral dosage form comprising an active agent, a salt form of azelastine and a salt form of donepezil or rivastigmine or galantamine is effective in treating psychiatric, behavioral and cognitive disorders. found to be suitable for treating patients suffering from
[0019] 下記に提供される詳細な説明は、本発明の実施例の説明として意図され、本発明の実施例が構成されてもよい又は利用されてもよい唯一の形態を示すことを意図するものではない。説明は、実施例の働き及び実施例を構成し、運用するためのステップの順序について記載する。しかしながら、同じ又は等価な働き及び順序は、様々な実施例によって達成されてもよい。 [0019] The detailed description provided below is intended as a description of embodiments of the invention and is intended to represent the only forms in which embodiments of the invention may be constructed or utilized. not a thing The description sets forth the operation of the embodiment and the sequence of steps for making and operating the embodiment. However, the same or equivalent functions and sequences may be achieved by various embodiments.
[0020]定義
[0021] 本明細書において使用されるように、以下の語及び句は、語及び句が使用される文脈において特に明記されない限り、下記に記載される意味を有することが概して意図される。
[0020] Definition
[0021] As used herein, the following terms and phrases are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which the terms and phrases are used.
[0022] 精神、行動、認知障害は、アルツハイマー病、認知症、パーキンソン病、ハンチントン病、及びそのいずれかの組み合わせ並びに他の神経変性障害を含むことができるが、これらに限定されない。 [0022] Psychiatric, behavioral, cognitive disorders can include, but are not limited to, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, and any combination thereof and other neurodegenerative disorders.
[0023] 本明細書において使用されるように、「ドネペジル」という用語は、ドネペジル遊離塩基、２，３－ジヒドロ－５，６－ジメトキシ－２－［［１－（フェニルメチル）－４－ピペリジニル］メチル］－１Ｈ－インデン－１－オンを指す。ある特定の実施形態では、ドネペジルはまた、塩酸塩又はＨＣｌ塩などの、任意の薬学的に許容される塩をも含む。好ましくは、本明細書において記載される本発明の任意の実施形態において、ドネペジルは、ドネペジル塩酸塩又はドネペジルＨＣｌのように、その塩酸塩の形態をしている。より好ましくは、本明細書において記載される本発明の任意の実施形態において、経口投薬形態におけるドネペジルの量及び投薬範囲への言及は、ドネペジル塩酸塩の量及び投薬範囲に対するものである。 [0023] As used herein, the term "donepezil" refers to donepezil free base, 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl ]methyl]-1H-inden-1-one. In certain embodiments, donepezil also includes any pharmaceutically acceptable salt, such as the hydrochloride or HCl salt. Preferably, in any of the embodiments of the invention described herein, donepezil is in the form of its hydrochloride salt, such as donepezil hydrochloride or donepezil HCl. More preferably, in any embodiment of the invention described herein, references to amounts and dosage ranges of donepezil in oral dosage forms are to amounts and dosage ranges of donepezil hydrochloride.
[0024] 本明細書において使用されるように、「リバスチグミン」という用語は、リバスチグミン遊離塩基、（Ｓ）－３－（１－（ジメチルアミノ）エチル）フェニルエチル（メチル）カルバメートを指す。ある特定の実施形態において、リバスチグミンはまた、酒石酸塩などの、任意の薬学的に許容される塩をも含む。好ましくは、本明細書において記載される本発明の任意の実施形態において、リバスチグミンは、リバスチグミン酒石酸塩のように、その酒石酸塩の形態をしている。より好ましくは、本明細書において記載される本発明の任意の実施形態において、経口投薬形態におけるリバスチグミンの量及び投薬範囲への言及は、リバスチグミン酒石酸塩の量及び投薬範囲に対するものである。 [0024] As used herein, the term "rivastigmine" refers to rivastigmine free base, (S)-3-(1-(dimethylamino)ethyl)phenylethyl(methyl)carbamate. In certain embodiments, rivastigmine also includes any pharmaceutically acceptable salt, such as the tartrate. Preferably, in any embodiment of the invention described herein, rivastigmine is in the form of its tartrate salt, such as rivastigmine tartrate. More preferably, in any embodiment of the invention described herein, references to amounts and dosage ranges of rivastigmine in oral dosage forms are to amounts and dosage ranges of rivastigmine tartrate.
[0025] 本明細書において使用されるように、「ガランタミン」という用語は、ガランタミン遊離塩基、（４ａＳ，６Ｒ，８ａＳ）－５，６，９，１０，１１，１２－ヘキサヒドロ－３－メトキシ－１１－メチル－４ａＨ－［１］ベンゾフロ［３ａ，３，２－ｅｆ］［２］ベンゾアゼピン－６－オールを指す。ある特定の実施形態において、ガランタミンはまた、臭化水素塩などの、任意の薬学的に許容される塩をも含む。好ましくは、本明細書において記載される本発明の任意の実施形態において、ガランタミンは、ガランタミン臭化水素酸塩又はガランタミンＨＢｒのように、その臭化水素塩の形態をしている。より好ましくは、本明細書において記載される本発明の任意の実施形態において、経口投薬形態におけるガランタミンの量及び投薬範囲への言及は、ガランタミン臭化水素酸塩の量及び投薬範囲に対するものである。 [0025] As used herein, the term "galantamine" refers to galantamine free base, (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy- It refers to 11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol. In certain embodiments, galantamine also includes any pharmaceutically acceptable salt, such as hydrobromide. Preferably, in any embodiment of the invention described herein, galantamine is in the form of its hydrobromide salt, such as galantamine hydrobromide or galantamine HBr. More preferably, in any embodiment of the invention described herein, references to amounts and dosage ranges of galantamine in oral dosage forms are to amounts and dosage ranges of galantamine hydrobromide. .
[0026] 本明細書において使用されるように、「アゼラスチン」という用語は、アゼラスチン遊離塩基、すなわち４－（ｐ－クロロベンジル）－２－（ヘキサヒドロ－１－メチル－１Ｈ－アゼピン－４－イル）－１－（２Ｈ）－フタラジノンを指す。ある特定の実施形態では、アゼラスチンはまた、塩酸塩又はＨＣｌ塩などの、任意の薬学的に許容される塩をも含む。好ましくは、本明細書において記載される本発明の任意の実施形態において、アゼラスチンは、アゼラスチン塩酸塩又はアゼラスチンＨＣｌのように、その塩酸塩の形態をしている。より好ましくは、本明細書において記載される本発明の任意の実施形態において、経口投薬形態におけるアゼラスチンの量及び投薬範囲への言及は、アゼラスチン塩酸塩の量及び投薬範囲に対するものである。 [0026] As used herein, the term "azelastine" refers to azelastine free base, namely 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl )-1-(2H)-phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HCl salt. Preferably, in any embodiment of the invention described herein, azelastine is in the form of its hydrochloride salt, such as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the invention described herein, references to amounts and dosage ranges of azelastine in oral dosage forms are to amounts and dosage ranges of azelastine hydrochloride.
[0027] 本明細書において使用されるように、「治療すること」若しくは「治療」は、完全な治癒若しくは不完全な治癒を意味する、すなわち、それは、根底にある疾患若しくは関連する状態の症状が、少なくとも低下する及び／又は遅延する及び／又は症状を引き起こしている、根底にある細胞の、生理学的、若しくは生化学的原因若しくはメカニズムの１つ以上が、低下する、遅延する、及び／又は取り除かれることを意味する。低下する又は遅延するとは、これに関連して使用されるように、未治療の疾患の状況に関して、未治療の疾患の生理学的状況だけではなく、未治療の疾患の分子的状況を含むことを意味すると理解される。 [0027] As used herein, "treating" or "treatment" means complete or incomplete cure, i.e., it treats symptoms of an underlying disease or related condition. is at least reduced and/or delayed and/or one or more of the underlying cellular, physiological or biochemical causes or mechanisms causing symptoms are reduced, delayed and/or means removed. Decrease or retard, as used in this context, refers to the status of an untreated disease and is intended to include not only the physiological status of the untreated disease, but also the molecular status of the untreated disease. understood to mean
[0028] 「有効量」という用語は、そのような治療を必要とする哺乳動物に投与される場合に、下記に定義されるように、治療を成し遂げるのに十分である量を指す。治療有効量は、治療されている患者、患者の体重及び年齢、疾患状態の重症度、投与の方式、並びにその他同種のものに応じて変動し、これらは、当業者によって容易に決定することができる。医薬組成物は、経口投与によって、単回投与又は反復投与で投与されてもよい。投与は、カプセル、錠剤、又はその他同種のものを介してのものであってもよい。 [0028] The term "effective amount" refers to an amount that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined below. A therapeutically effective amount will vary depending on the patient being treated, the weight and age of the patient, the severity of the disease state, the mode of administration, and the like, and can be readily determined by those skilled in the art. can. Pharmaceutical compositions may be administered by oral administration, in single or multiple doses. Administration may be via capsules, tablets, or the like.
[0029] 本明細書において定量測定に関連して使用される「約」という用語は、示される量±１０％を意味する。例えば、±１０％の範囲では、「約５ｍｇ」は、４．５～５．５ｍｇを意味することができる。 [0029] The term "about," as used herein in connection with quantitative measurements, means ± 10% of the indicated amount. For example, within ±10%, "about 5 mg" can mean 4.5-5.5 mg.
[0030] 医薬組成物は、当技術分野において知られている方法、例えばAnsel’s Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013)及びHandbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6 by Sarfaraz K. Niazi)を使用して、医薬として使用するために製剤されてもよい。したがって、活性化合物及び放出制御又は緩効性マトリックスの組み込みが、実行されてもよい。 [0030] Pharmaceutical compositions can be prepared by methods known in the art, such as Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6 by Sarfaraz K. Niazi) may be formulated for pharmaceutical use. Thus, the incorporation of active compounds and controlled-release or slow-release matrices may be practiced.
[0031] 液体又は固体単位投薬形態は、経口投与のために容易に調製することができる。例えば、医薬賦形剤又はキャリアとしてのリン酸二カルシウム、ケイ酸アルミウニムマグネシウム、ステアリン酸マグネシウム、硫酸カルシウム、デンプン、滑石、ラクトース、アカシア、メチルセルロース、及び機能的に類似する材料などの従来の成分と混ぜられる。徐放性製剤が、任意選択で使用されてもよい。高齢の又は思考散乱状態の対象において、徐放性製剤は、さらに好ましくてもよい。カプセルは、医薬希釈剤と化合物を混合すること及びこの混合物を適切なサイズを有する硬ゼラチンカプセルの中に挿入することによって製剤されてもよい。軟カプセルが所望される場合、許容される植物油、石油エーテル、又は他の不活性油との化合物のスラリーは、ゼラチンカプセルを形成することによってカプセル化することができる。 [0031] Liquid or solid unit dosage forms can be readily prepared for oral administration. For example, conventional formulations such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical excipients or carriers. mixed with ingredients. Sustained release formulations may optionally be used. In elderly or thought-distracted subjects, sustained release formulations may be more preferred. Capsules may be prepared by mixing the compound with a pharmaceutical diluent and inserting the mixture into an appropriately sized hard gelatin capsule. If a soft capsule is desired, a slurry of the compound with an acceptable vegetable oil, petroleum ether, or other inert oil can be encapsulated by forming a gelatin capsule.
[0032] 懸濁剤、シロップ、及びエリキシルは、経口投与又は流体単位投薬形態用に使用されてもよい。油を含む流体調製物は、油溶性の形態用に使用されてもよい。トウモロコシ油、ピーナッツ油、又は花精油などの植物油は、例えば、香料、甘味料、及び任意の防腐剤と共に、許容される流体調製物を生成する。界面活性剤は、流体単位投薬用のシロップを形成するために水に追加されてもよい。糖、サッカリン、又は生物学的甘味料などの、許容される甘味料及び香味料を有するヒドロアルコール性医薬調製物は、エリキシルの形態で使用されてもよい。 [0032] Suspensions, syrups, and elixirs may be used for oral administration or for fluid unit dosage forms. Oil-containing fluid formulations may be used for oil-soluble forms. Vegetable oils such as corn, peanut, or flower essential oils, for example, along with flavors, sweeteners, and optional preservatives, make acceptable fluid preparations. A surfactant may be added to water to form a syrup for fluid unit dosage. Hydroalcoholic pharmaceutical preparations with acceptable sweetening and flavoring agents, such as sugar, saccharin, or biological sweeteners, may also be used in the form of elixirs.
[0033] 本開示の固体経口投薬製剤は、錠剤、カプレット、二層錠剤、フィルムコーティング錠剤、丸剤、カプセル、又はその他同種のものの形態を意味する。本開示に従う錠剤は、医薬製剤産業においてよく知られている任意の混合及び錠剤化技術によって調製することができる。いくつかの実施例では、投薬製剤は、回転式打錠機に取り付けられたパンチ及びダイによって、それぞれ調製された徐放性部分及び即効性部分を直接圧縮すること、射出成形若しくは圧縮成形、又は造粒、続く圧縮によって作られる。 [0033] A solid oral dosage form of the present disclosure means a form of tablet, caplet, bilayer tablet, film-coated tablet, pill, capsule, or the like. Tablets according to the present disclosure can be prepared by any of the mixing and tabletting techniques well known in the pharmaceutical formulation industry. In some embodiments, the dosage formulation is formed by direct compression, injection molding or compression molding, or Made by granulation followed by compression.
[0034] 本開示に従って提供される医薬組成物は、普通、経口投与される。本開示は、そのため、本明細書において記載されるアゼラスチン及びドネペジル又はリバスチグミン又はガランタミンを含む固体分散剤並びに不活性固体希釈剤及び増量剤、滅菌水溶液及び様々な有機溶媒を含む希釈剤、浸透促進剤、可溶化剤、崩壊剤、潤滑剤、バインダー、流動化剤、佐剤、並びにその組み合わせを含むが、これらに限定されない１つ以上の薬学的に許容される賦形剤又はキャリアを含む医薬組成物を提供する。そのような組成物は、医薬の技術においてよく知られている方式で調製される（例えばAnsel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by Loyd Allen, 2013)及びHandbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6 by Sarfaraz K. Niazi)を参照）。 [0034] The pharmaceutical compositions provided according to this disclosure are typically administered orally. The present disclosure therefore provides solid dispersions comprising azelastine and donepezil or rivastigmine or galantamine as described herein as well as inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients or carriers including, but not limited to, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof offer things. Such compositions are prepared in a manner well known in the pharmaceutical art (e.g. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1- 6 by Sarfaraz K. Niazi).
[0035] 医薬組成物は、希釈剤、バインダー、増量剤、流動化剤、崩壊剤、潤滑剤、可溶化剤、及びその組み合わせなどの医薬賦形剤をさらに含んでいてもよい。適した賦形剤のいくつかの例は、本明細書において記載される。医薬組成物が錠剤に製剤される場合、錠剤は、胃腸管における崩壊及び吸着を遅延させるために、マイクロカプセル化を含む既知の技術によってコーティングされなくてもコーティングされてもよく、それによって、より長い期間にわたって持続性の作用をもたらしてもよい。例えば、モノステアリン酸グリセリン又はジステアリン酸グリセリルなどの時間遅延物質は、単独で又はワックスと共に用いられてもよい。 [0035] The pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated in tablets, the tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby increasing May provide a sustained effect over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
[0036] 実施形態において、医薬組成物は、ａ）約４ｍｇ～２０ｍｇのアゼラスチンＨＣｌ（若しくはその他の塩）及びｂ）約１ｍｇ～４ｍｇのドネペジルＨＣｌ若しくは約１ｍｇ～２ｍｇのリバスチグミン酒石酸塩若しくは約１ｍｇ～３ｍｇのガランタミンＨＢｒ又はａ）約８ｍｇ～１６ｍｇのアゼラスチンＨＣｌ（若しくはその他の塩）及びｂ）約１ｍｇ～４ｍｇのドネペジルＨＣｌ若しくは約１ｍｇ～２ｍｇのリバスチグミン酒石酸塩若しくは約１ｍｇ～３ｍｇのガランタミンＨＢｒ又はａ）約１０ｍｇ～１４ｍｇのアゼラスチンＨＣｌ（若しくはその他の塩）及びｂ）約１ｍｇ～４ｍｇのドネペジルＨＣｌ若しくは約１ｍｇ～２ｍｇのリバスチグミン酒石酸塩若しくは約１ｍｇ～３ｍｇのガランタミンＨＢｒを含むことができる。例えば、組成物は、ａ）約１２ｍｇのアゼラスチンＨＣｌ及びｂ）約４ｍｇのドネペジルＨＣｌ又は約２ｍｇのリバスチグミン酒石酸塩又は約３ｍｇのガランタミンＨＢｒを含むことができる。さらに、例えば、本発明の組成物は、約４ｍｇ～約５０ｍｇの範囲の量で存在するアゼラスチン又はアゼラスチンの薬学的に許容される塩及び約１ｍｇ～約４ｍｇの範囲の量のドネペジルＨＣｌ又は約１ｍｇ～約２ｍｇの範囲の量のリバスチグミン酒石酸塩又は約１ｍｇ～約３ｍｇの範囲の量のガランタミンＨＢｒを含むことができる。実施形態において、組成物中に存在するアゼラスチンＨＣｌ（又はその他の塩）の量は、組成物中に存在するドネペジルＨＣｌ又はリバスチグミン酒石酸塩又はガランタミンＨＢｒ（又はその他の塩）の量と等しい、それを超える、又はそれ未満のものとすることができる。実施形態において、組成物中に存在するアゼラスチンＨＣｌ（及び／又はその他の塩）の量は、組成物中に存在するドネペジルＨＣｌ又はリバスチグミン酒石酸塩又はガランタミンＨＢｒ（及び／又はその他の塩）の量の２倍又は３倍又は４、５、６、７、８、９、１０、１５、２０、２５、３０、３５、４０、４５、若しくは５０倍とすることができるし、又はその逆も言える。本発明の組成物の任意の１つ以上は、本明細書において開示される任意の１つ以上の本発明の方法又は組成物を使用する他の方法で使用することができる。 [0036] In embodiments, the pharmaceutical composition comprises a) about 4-20 mg azelastine HCl (or other salt) and b) about 1-4 mg donepezil HCl or about 1-2 mg rivastigmine tartrate or about 1-2 mg rivastigmine tartrate. 3 mg galantamine HBr or a) about 8 mg to 16 mg azelastine HCl (or other salt) and b) about 1 mg to 4 mg donepezil HCl or about 1 mg to 2 mg rivastigmine tartrate or about 1 mg to 3 mg galantamine HBr or a) about 10 mg to 14 mg azelastine HCl (or other salt) and b) about 1 mg to 4 mg donepezil HCl or about 1 mg to 2 mg rivastigmine tartrate or about 1 mg to 3 mg galantamine HBr. For example, the composition can comprise a) about 12 mg azelastine HCl and b) about 4 mg donepezil HCl or about 2 mg rivastigmine tartrate or about 3 mg galantamine HBr. Further, for example, compositions of the present invention may include azelastine or a pharmaceutically acceptable salt of azelastine present in an amount ranging from about 4 mg to about 50 mg and donepezil HCl in an amount ranging from about 1 mg to about 4 mg or about 1 mg. rivastigmine tartrate in an amount ranging from to about 2 mg or galantamine HBr in an amount ranging from about 1 mg to about 3 mg. In embodiments, the amount of azelastine HCl (or other salt) present in the composition is equal to the amount of donepezil HCl or rivastigmine tartrate or galantamine HBr (or other salt) present in the composition. can be greater than or less than In embodiments, the amount of azelastine HCl (and/or other salts) present in the composition is less than the amount of donepezil HCl or rivastigmine tartrate or galantamine HBr (and/or other salts) present in the composition. It can be two times or three times or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 times, or vice versa. Any one or more of the compositions of the invention can be used in any one or more of the methods of the invention disclosed herein or other methods of using the compositions.
[0037] 実際に投与されるアゼラスチンＨＣｌ及びドネペジルＨＣｌ又はリバスチグミン酒石酸塩又はガランタミンＨＢｒを含有する医薬組成物の量は、普通、治療される状態、選ばれる投与ルート、投与される実際の化合物及びその相対的活性、個々の患者の年齢、体重、及び反応、患者の症状の重症度、並びにその他同種のものを含む関連する状況に照らして、医師によって決定されることが理解されるであろう。 [0037] The amount of pharmaceutical composition containing azelastine HCl and donepezil HCl or rivastigmine tartrate or galantamine HBr actually administered will normally depend on the condition being treated, the route of administration chosen, the actual compound administered and its It will be understood that it will be determined by the physician in the light of relevant circumstances, including relative activity, age, weight and response of the individual patient, severity of the patient's symptoms, and the like.
[0038] 本明細書において記載されるアゼラスチンＨＣｌ及びドネペジルＨＣｌ又はリバスチグミン酒石酸塩又はガランタミンＨＢｒを含有する医薬組成物、医薬投薬形態、及び錠剤は、アルツハイマー病などの神経変性障害に罹患している患者に、１日１回、１日２回、２日に１回、週２回、週３回、週４回、又は週５回、経口投与によって投与される。 [0038] Pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing azelastine HCl and donepezil HCl or rivastigmine tartrate or galantamine HBr described herein are useful in patients suffering from neurodegenerative disorders such as Alzheimer's disease. by oral administration once daily, twice daily, once every other day, twice weekly, three times weekly, four times weekly, or five times weekly.
[0039] 実施形態において、患者は、８ｍｇ～約１６ｍｇの範囲のアゼラスチンＨＣｌ及び約１ｍｇ～約４ｍｇの範囲の量のドネペジルＨＣｌ又は約１ｍｇ～約２ｍｇの範囲の量のリバスチグミン酒石酸塩又は約１ｍｇ～約３ｍｇの範囲の量のガランタミンＨＢｒの治療に有効な１日投与量を有する医薬組成物を投与される。 [0039] In embodiments, the patient is administered azelastine HCl in an amount ranging from 8 mg to about 16 mg and donepezil HCl in an amount ranging from about 1 mg to about 4 mg or rivastigmine tartrate in an amount ranging from about 1 mg to about 2 mg or rivastigmine tartrate in an amount ranging from about 1 mg to about 1 mg. A pharmaceutical composition having a therapeutically effective daily dose of galantamine HBr in an amount in the range of about 3 mg is administered.
[0040] 実施形態において、本明細書において記載されるアゼラスチンＨＣｌ及びドネペジルＨＣｌ又はリバスチグミン酒石酸塩又はガランタミンＨＢｒを含有する医薬組成物の医薬投薬形態及び錠剤は、約６～２４週間でアルツハイマー病を有する患者において症状を逆転させることにおいて有効である。 [0040] In embodiments, pharmaceutical dosage forms and tablets of pharmaceutical compositions containing azelastine HCl and donepezil HCl or rivastigmine tartrate or galantamine HBr described herein have Alzheimer's disease in about 6-24 weeks. Effective in reversing symptoms in patients.
[0041] ＡＤを有する患者に対する医薬組成物の治療の有効性は、ミニメンタルステート検査（ＭＭＳＥ）並びに０～３の重症度スコア及び０～５の窮迫スコアを有する１２の神経心理検査（ＮＰＩ－Ｑ）のスコアの改善によって評価される。 [0041] The efficacy of treatment of pharmaceutical compositions for patients with AD is assessed by the Mini-Mental State Examination (MMSE) and 12 Neuropsychological Examinations (NPI-12) with a severity score of 0-3 and a distress score of 0-5. It is evaluated by the improvement of the score of Q).
[0042] ＡＤの治療について、アセチルコリンエステラーゼ阻害剤の１つとして、ドネペジルのみで、ＭＭＥＳを９．２％及び全ＮＰＩを４０．９％及びＮＰＩ窮迫を４１．５％改善する。 [0042] For the treatment of AD, donepezil alone, as an acetylcholinesterase inhibitor, improves MMES by 9.2% and total NPI by 40.9% and NPI distress by 41.5%.
[0043] 以下の実施例は、例証であり、主張される主題の範囲を限定するものと解釈されるべきではない。 [0043] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.
[0044]実施例１
[0045] １０～１の範囲にわたるＭＭＳＥスコア並びに３の重症度スコア及び４又は５の窮迫スコアを有するＮＰＩ－Ｑを有する末期アルツハイマー病と診断される１０人の患者を、１日１回、１２ｍｇのアゼラスチンＨＣｌ及び３ｍｇのドネペジルＨＣｌを含有する、錠剤の形態の医薬組成物により治療する。１２週間後、これら１０人の患者のＭＭＳＥスコアは、ＭＭＳＥスコアにおける１～９倍の改善である２０～１０の範囲まで、少なくとも９増加することが期待されるであろう、また、患者らのＮＰＩ－Ｑは、２．５～４倍の改善である１の重症度スコア及び１又は２の窮迫スコアを有することが期待されるであろう。
[0044] Example 1
[0045] Ten patients diagnosed with end-stage Alzheimer's disease with an MMSE score ranging from 10 to 1 and an NPI-Q with a severity score of 3 and a distress score of 4 or 5 were treated with 12 mg once daily. of azelastine HCl and 3 mg of donepezil HCl in tablet form. After 12 weeks, the MMSE scores of these 10 patients would be expected to increase by at least 9 to a range of 20-10, which is a 1-9 fold improvement in MMSE scores. The NPI-Q would be expected to have a severity score of 1 and a distress score of 1 or 2, which is a 2.5-4 fold improvement.
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[0070]M. Farlow, F. Veloso, M. Moline et al., “Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer’s disease,” BMC Neurology, vol. 11, article 57, 2011.
[0071]E. Schwam and Y. Xu, “Cognition and function in Alzheimer’s disease: Identifying the transitions from moderate to severe disease,” Dementia and Geriatric Cognitive Disorders, vol. 29, no. 4, pp. 309-316, 2010.
[0072]A. Homma, Y. Imai, H. Tago et al., “Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 5, pp. 399-407, 2008.
[0073]S. E. Black, R. Doody, H. Li et al., “Donepezil preserves cognition and global function in patients with severe Alzheimer disease,” Neurology, vol. 69, no. 5, pp. 459-469, 2007.
[0074]M. R. Farlow, M. L. Miller, and V. Pejovic, “Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 5, pp. 408-422, 2008.
[0075]A. K. Wallin, N. Andreasen, S. Eriksson et al., “Donepezil in Alzheimer’s disease: what to expect after 3 years of treatment in a routine clinical setting,” Dementia and Geriatric Cognitive Disorders, vol. 23, no. 3, pp. 150-160, 2007.
[0076]D. Galasko, F. Schmitt, R. Thomas, S. Jin, D. Bennett, and S. Ferris, “Detailed assessment of activities of daily living in moderate to severe Alzheimer’s disease,” Journal of the International Neuropsychological Society, vol. 11, no. 4, pp. 446-453, 2005.
[0077]D. Wilkinson, R. Schindler, E. Schwam et al., “Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate Alzheimer’s disease,” Dementia and Geriatric Cognitive Disorders, vol. 28, no. 3, pp. 244-251, 2009.
[0078]M. Bond, G. Rogers, J. Peters et al., “The effectiveness and cost effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease: a systematic review and economic model,” NIHR HTA Programme Project Number 09/87/01, National Institute for Clinical Excellence, London, UK, 2010.
[0079]A. Atri, L. W. Shaughnessy, J. J. Locascio, and J. H. Growdon, “Long-term course and effectiveness of combination therapy in Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 22, no. 3, pp. 209-221, 2008.
[0080]A. Atri, S. D. Rountree, O. L. Lopez, and R. S. Doody, “Validity, significance, strengths, limitations, and evidentiary value of real-world clinical data for combination therapy in Alzheimer’s disease: comparison of efficacy and effectiveness studies,” Neurodegenerative Diseases, vol. 10, no. 1-4, pp. 170-174, 2012.
[0081]C. W. Zhu and M. Sano, “Economic considerations in the management of Alzheimer’s disease,” Clinical interventions in aging, vol. 1, no. 2, pp. 143-154, 2006.
[0082]Epstein AB, van Hoven PT, Kaufman A, Carr WW. Management of allergic conjunctivitis: An evaluation of the perceived comfort and therapeutic efficacy of olopatadine 0.2% and azelastine 0.05% from two prospective studies. Clin Ophthalmol. 2009;3:329-336.
[0083]Bielory L, Bielory B. Ocular allergy: An allergist’s perspective. Aug 16, 2010.
[0084]Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care. 2008;14 Suppl 3:S102-S106.
[0085]Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs. 2005; 65:215-218.
[0086]Bielory L, Buddiga P, Bigelsen S. Ocular allergy treatment comparisons: Azelastine and olopatadine. Curr Allergy Asthma Rep. 2004;4:320-325.
[0087]Baudouin C. Detrimental effect of preservative in eye drops: Implications for the treatment of glaucoma. Acta Ophthalmologica. 2008;86:716-726.
[0088]Lee JS, Lee JE, Kim N, Oum BS. Comparison of the conjunctival toxicity of topical ocular antiallergic agents. J Ocul Pharmacol Ther. 2008;24:557-562.
[0089]Lambiase A, Micera A, Bonini S. Multiple action agents and the eye: Do they really stabilize mast cells? Curr Opin Allergy Clin Immunol. 2009;9:454-465.
[0090]Casale T. The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989;83:771-776.
[0091]Hazama H, Nakajima T, Hisada T, Hamada E, Omata M, Kurachi Y. Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig. Eur J Pharmacol. 1994;259: 143-150.
[0092]Perhach JL, Connell JT, Kemp JP. Treatment of upper and lower airway disease with azelastine. N Engl Reg Allergy Proc. 1987;8:121-124.
[0093]Szelenyi I, Achterrath-Tuckermann U, Schmidt J, Minker E, Paegelow I, Werner H. Azelastine: A multifaceted drug for asthma therapy. Agents Actions Suppl. 1991;34:295-311.
[0094]Galatowicz G, Ajayi Y, Stern ME, Calder VL. Ocular antiallergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo. Clin Exp Allergy. 2007;37:1648-1656.
[0095]Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: An antiallergic activity. J Allergy Clin Immunol. 1996;98(6 Pt 1):1088-1096.
[0096]Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999;36:329-352.
[0097]Boada-Rovira M, Brodaty H, et al. Efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a global, multinational, clinical experience study. Drugs Aging. 2004;21(1):43-53.
[0098]Holmes C, Wilkinson D, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004 Jul 27;63(2):214-9.
[0099]Loyd Allen, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013)
[00100]Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.
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[0064] RA Hansen, G. Gartlehner, AP Webb, LC Morgan, CG Moore, and DE Jonas, "Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis," Clinical Interventions in Aging, vol. 3, no. 2, pp. 211-225, 2008.
[0065] DD Christensen, "Higher-dose (23 mg/day) donepezil formulation for the treatment of patients with moderate-to-severe Alzheimer's disease," Postgraduate Medicine, vol. 124, no. 6, pp. 110-116, 2012.
[0066] JL Cummings, D. Geldmacher, M. Farlow, M. Sabbagh, D. Christensen, and P. Betz, “High-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer's disease: drug profile and clinical guidelines,” CNS Neuroscience & Therapeutics, vol. 19, no. 5, pp. 294-301, 2013.
[0067] S. Ferris, J. Cummings, D. Christensen et al., "Effects of donepezil 23 mg on Severe Impairment Battery domains in patients with moderate-to-severe Alzheimer's disease: evaluating the impact of baseline severity,"Alzheimer's Research & Therapy, vol. 5, no. 1, article 12, 2013.
[0068] MM Carrasco, L. Aguera, P. Gil, A. Morinigo, and T. Leon, “Safety and effectiveness of donepezil on behavioral symptoms in patients with Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 25, no 4, pp. 333-340, 2011.
[0069] MR Farlow, S. Salloway, PN Tariot et al., “Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: a 24 -week, randomized, double-blind study,” Clinical Therapeutics, vol. 32, no. 7, pp. 1234-1251, 2010.
[0070]M. Farlow, F. Veloso, M. Moline et al., “Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease,” BMC Neurology, vol. 11, article 57, 2011.
[0071] E. Schwam and Y. Xu, “Cognition and function in Alzheimer's disease: Identifying the transitions from moderate to severe disease,” Dementia and Geriatric Cognitive Disorders, vol. 29, no. 4, pp. 309-316, 2010 .
[0072] A. Homma, Y. Imai, H. Tago et al., “Donepezil treatment of patients with severe Alzheimer's disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial, ”Dementia and Geriatric Cognitive Disorders, vol. 25, no. 5, pp. 399-407, 2008.
[0073] SE Black, R. Doody, H. Li et al., “Donepezil preserves cognition and global function in patients with severe Alzheimer disease,” Neurology, vol. 69, no. 5, pp. 459-469, 2007.
[0074] MR Farlow, ML Miller, and V. Pejovic, "Treatment options in Alzheimer's disease: maximizing benefit, managing expectations," Dementia and Geriatric Cognitive Disorders, vol. 25, no. 5, pp. 408-422, 2008.
[0075] AK Wallin, N. Andreasen, S. Eriksson et al., “Donepezil in Alzheimer's disease: what to expect after 3 years of treatment in a routine clinical setting,” Dementia and Geriatric Cognitive Disorders, vol. 23, no. 3, pp. 150-160, 2007.
[0076] D. Galasko, F. Schmitt, R. Thomas, S. Jin, D. Bennett, and S. Ferris, “Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease,” Journal of the International Neuropsychological Society , vol. 11, no. 4, pp. 446-453, 2005.
[0077] D. Wilkinson, R. Schindler, E. Schwam et al., “Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 28, no. 3, pp. 244-251, 2009.
[0078] M. Bond, G. Rogers, J. Peters et al., “The effectiveness and cost effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease: a systematic review and economic model,” NIHR HTA Programme. Project Number 09/87/01, National Institute for Clinical Excellence, London, UK, 2010.
[0079] A. Atri, LW Shaughnessy, JJ Locascio, and JH Growdon, “Long-term course and effectiveness of combination therapy in Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 22, no. 3, pp. 209- 221, 2008.
[0080] A. Atri, SD Rountree, OL Lopez, and RS Doody, “Validity, significance, strengths, limitations, and evidentiary value of real-world clinical data for combination therapy in Alzheimer's disease: comparison of efficacy and effectiveness studies,” Neurodegenerative Diseases, vol. 10, no. 1-4, pp. 170-174, 2012.
[0081]CW Zhu and M. Sano, “Economic considerations in the management of Alzheimer's disease,” Clinical interventions in aging, vol. 1, no. 2, pp. 143-154, 2006.
[0082] Epstein AB, van Hoven PT, Kaufman A, Carr WW. Management of allergic conjunctivitis: An evaluation of the perceived comfort and therapeutic efficacy of olopatadine 0.2% and azelastine 0.05% from two prospective studies. Clin Ophthalmol. 2009;3: 329-336.
[0083]Bielory L, Bielory B. Ocular allergy: An allergist's perspective. Aug 16, 2010.
[0084] Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care. 2008;14 Suppl 3:S102-S106.
[0085] Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs. 2005; 65:215-218.
[0086] Bielory L, Buddiga P, Bigelsen S. Ocular allergy treatment comparisons: Azelastine and olopatadine. Curr Allergy Asthma Rep. 2004;4:320-325.
[0087] Baudouin C. Detrimental effect of preservative in eye drops: Implications for the treatment of glaucoma. Acta Ophthalmologica. 2008;86:716-726.
[0088] Lee JS, Lee JE, Kim N, Oum BS. Comparison of the conjunctival toxicity of topical ocular antiallergic agents. J Ocul Pharmacol Ther. 2008;24:557-562.
[0089] Lambiase A, Micera A, Bonini S. Multiple action agents and the eye: Do they really stabilize mast cells? Curr Opin Allergy Clin Immunol. 2009;9:454-465.
[0090] Casale T. The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989;83:771-776.
[0091] Hazama H, Nakajima T, Hisada T, Hamada E, Omata M, Kurachi Y. Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig. Eur J Pharmacol. 1994;259: 143-150 .
[0092] Perhach JL, Connell JT, Kemp JP. Treatment of upper and lower airway disease with azelastine. N Engl Reg Allergy Proc. 1987;8:121-124.
[0093] Szelenyi I, Achterrath-Tuckermann U, Schmidt J, Minker E, Paegelow I, Werner H. Azelastine: A multifaceted drug for asthma therapy. Agents Actions Suppl. 1991;34:295-311.
[0094] Galatowicz G, Ajayi Y, Stern ME, Calder VL. Ocular antiallergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo. Clin Exp Allergy. 2007;37:1648-1656.
[0095] Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: An antiallergic activity. J Allergy Clin Immunol. 1996;98(6 Pt 1): 1088-1096.
[0096]Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999;36:329-352.
[0097] Boada-Rovira M, Brodaty H, et al. Efficacy and safety of donepezil in patients with Alzheimer's disease: results of a global, multinational, clinical experience study. Drugs Aging. 2004;21(1):43-53.
[0098] Holmes C, Wilkinson D, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004 Jul 27;63(2):214-9.
[0099] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013)
[00100] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.
[00101] 本発明は、様々な特徴を有する特定の実施形態に関して記載された。上記に提供される本開示を考慮して、様々な修飾及び変形を、本発明の範囲又は精神から逸脱することなく、本発明の実施においてなすことができることは当業者らに明らかであろう。当業者は、開示される特徴が、単独で、任意の組み合わせで使用されてもよい、又は所定の用途若しくは設計の要求及び仕様に基づいて省かれてもよいことを認識するであろう。実施形態が、ある特定の特徴を「含む」ことを示す場合、実施形態が、その代わりに、任意の１つ以上の特徴「からなる」又は「から実質的になる」ことができることが理解されるべきである。本明細書において開示される方法のいずれも、本明細書において開示される組成物のいずれかと共に又は任意の他の組成物と共に使用することができる。同様に、開示される組成物のいずれも、本明細書において開示される方法のいずれかと共に又は任意の他の方法と共に使用することができる。本発明の他の実施形態は、本発明の明細書及び実施を考慮して当業者らに明らかになるであろう。 [00101] The invention has been described in terms of specific embodiments having various features. In view of the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the invention without departing from the scope or spirit of the invention. Those skilled in the art will recognize that the disclosed features may be used singly, in any combination, or omitted based on the needs and specifications of a given application or design. Where an embodiment is indicated as "comprising" a particular feature, it is understood that the embodiment may instead "consist of" or "consist essentially of" any one or more of the features. should. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other composition. Similarly, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other method. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.
[00102] 値の範囲が本明細書において提供される場合、その範囲の上限及び下限の間のそれぞれの値もまた、開示される単位の１０分の１まで、明確に開示されることが特に注意されたい。開示される範囲内の又は開示される他の端点から導き出すことができる任意のより小さな範囲もまた、それら自体、明確に開示される。開示される範囲の上限及び下限は、同様に、独立して、範囲に含まれてもよい又は除外されてもよい。単数形「１つの（a）」、「１つの（an）」、及び「その（the）」は、文脈上明らかに他の意味を示す場合を除き、複数形の指示対象を含む。本明細書及び実施例は本質的に例示的なものとみなされること、並びに本発明の本質から逸脱しない変形は本発明の範囲内に入ることが意図される。さらに、本開示において引用される参考文献はすべて、全体が本明細書において参照によってそれぞれ個々に組み込まれ、よって、本発明の実施可能な程度の開示を補足する効率的な手段を提供すること及び当業者のレベルを詳述する背景を提供することが意図される。
[00102] When a range of values is provided herein, it is expressly noted that each value between the upper and lower limits of the range is also specifically disclosed to the tenth of the unit disclosed. Please note. Any smaller range within the disclosed range or that can be derived from the other disclosed endpoints is also expressly disclosed as such. The upper and lower limits of the disclosed ranges may likewise, independently, be included in or excluded from the ranges. The singular forms "a,""an," and "the" include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the spirit of the invention are intended to be within the scope of the invention. Furthermore, all references cited in this disclosure are each individually incorporated herein by reference in their entireties, thus providing an efficient means of supplementing the enabling disclosure of the present invention; It is intended to provide background detailing the level of those skilled in the art.
Claims (21)
ドネペジル若しくはリバスチグミン若しくはガランタミン又はその薬学的に許容される塩又はその任意の組み合わせ、及び
１つ以上の薬学的に許容される賦形剤を含む、医薬組成物。 azelastine or a pharmaceutically acceptable salt of azelastine;
A pharmaceutical composition comprising donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof or any combination thereof, and one or more pharmaceutically acceptable excipients.
前記ドネペジル若しくはその薬学的に許容される塩は、約１ｍｇ～約４ｍｇの範囲の量で前記医薬組成物中に存在するか、又はリバスチグミン若しくはその塩は、約１ｍｇ～約２ｍｇの範囲で、又はガランタミン若しくはその塩は、約１ｍｇ～約３ｍｇの範囲で存在する、請求項１に記載の医薬組成物。 said azelastine or said pharmaceutically acceptable salt of azelastine is present in said pharmaceutical composition in an amount ranging from about 4 mg to about 50 mg;
The donepezil or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 4 mg, or rivastigmine or a salt thereof ranging from about 1 mg to about 2 mg, or 2. The pharmaceutical composition of Claim 1, wherein galantamine or a salt thereof is present in the range of about 1 mg to about 3 mg.
アゼラスチン又はアゼラスチンの薬学的に許容される塩、
ドネペジル若しくはリバスチグミン若しくはガランタミン又はその薬学的に許容される塩又はその任意の組み合わせ、及び
１つ以上の薬学的に許容される賦形剤
を含む医薬組成物の有効量を投与することを含み、
前記アゼラスチン及び／又はドネペジル及び／又はリバスチグミン及び／又はガランタミン又はその薬学的に許容される塩は、治療に相乗的な治療効果をもたらす量で前記組成物中に存在する、方法。 A method for treating a patient suffering from a mental, behavioral, or cognitive disorder, comprising:
azelastine or a pharmaceutically acceptable salt of azelastine;
administering an effective amount of a pharmaceutical composition comprising donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof or any combination thereof, and one or more pharmaceutically acceptable excipients;
The method wherein said azelastine and/or donepezil and/or rivastigmine and/or galantamine or a pharmaceutically acceptable salt thereof is present in said composition in an amount that provides a synergistic therapeutic effect.
前記ドネペジル又はその薬学的に許容される塩は約１ｍｇ～約４ｍｇ、又は前記リバスチグミンは約１ｍｇ～約２ｍｇ、又は前記ガランタミンは約１ｍｇ～約３ｍｇの範囲の量で、前記医薬組成物中に存在する、請求項１２に記載の方法。 said azelastine or said pharmaceutically acceptable salt of azelastine is present in said pharmaceutical composition in an amount ranging from about 4 mg to about 50 mg;
The donepezil or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 4 mg, or the rivastigmine from about 1 mg to about 2 mg, or the galantamine from about 1 mg to about 3 mg. 13. The method of claim 12, wherein
(i) azelastine or a pharmaceutically acceptable salt of azelastine, (ii) donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients Use of a composition comprising.
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|---|---|---|---|---|
| US11690849B2 (en) | 2019-04-12 | 2023-07-04 | LA PharmaTech Inc. | Method of treating dementia |
| US11744833B2 (en) | 2019-04-12 | 2023-09-05 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treatment of insomnia |
| US11938139B2 (en) | 2019-04-12 | 2024-03-26 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for anxiety, depression and other psychiatric disorders |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11318144B2 (en) | 2019-04-12 | 2022-05-03 | LA PharmaTech Inc. | Compositions and methods for treating Alzheimer's disease and Parkinson's disease |
| US10639314B1 (en) | 2019-04-30 | 2020-05-05 | LA PharmaTech Inc. | Method of treating Alzheimer's disease |
| US11389458B2 (en) | 2019-04-12 | 2022-07-19 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treating parkinson's and huntington's disease |
| US10966989B2 (en) | 2019-04-12 | 2021-04-06 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treating mental, behavioral, cognitive disorders |
| US11351179B1 (en) | 2021-08-05 | 2022-06-07 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treatment of psychiatric disorders |
| WO2024072049A1 (en) * | 2022-09-26 | 2024-04-04 | 주식회사 지투지바이오 | Pharmaceutical combination containing donepezil and rivastigmine for preventing, alleviating or treating dementia or cognitive impairment, and preparation method therefor |
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| JP2016529307A (en) * | 2013-09-09 | 2016-09-23 | サノフイ | H3 receptor antagonist for use in the treatment of Alzheimer's disease |
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| EP1431267A4 (en) * | 2001-08-09 | 2004-12-22 | Ono Pharmaceutical Co | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
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- 2019-05-21 AU AU2019446955A patent/AU2019446955A1/en not_active Abandoned
- 2019-05-21 CA CA3139082A patent/CA3139082A1/en active Pending
- 2019-05-21 JP JP2021566489A patent/JP2022539944A/en active Pending
- 2019-05-21 WO PCT/US2019/033359 patent/WO2020236159A1/en unknown
- 2019-05-21 EP EP19929933.0A patent/EP3973586A4/en active Pending
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| JP2012232978A (en) * | 2011-05-02 | 2012-11-29 | Lab Servier | New combination of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide and acetylcholinesterase inhibitor, and pharmaceutical composition including the same |
| JP2016529307A (en) * | 2013-09-09 | 2016-09-23 | サノフイ | H3 receptor antagonist for use in the treatment of Alzheimer's disease |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11690849B2 (en) | 2019-04-12 | 2023-07-04 | LA PharmaTech Inc. | Method of treating dementia |
| US11744833B2 (en) | 2019-04-12 | 2023-09-05 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treatment of insomnia |
| US11938139B2 (en) | 2019-04-12 | 2024-03-26 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for anxiety, depression and other psychiatric disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020236159A1 (en) | 2020-11-26 |
| EP3973586A1 (en) | 2022-03-30 |
| AU2019446955A1 (en) | 2021-12-23 |
| CN114072945A (en) | 2022-02-18 |
| CA3139082A1 (en) | 2020-11-26 |
| EP3973586A4 (en) | 2023-01-11 |
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