JP2023539405A - Compositions and methods for treating Alzheimer's disease and Parkinson's disease - Google Patents
Compositions and methods for treating Alzheimer's disease and Parkinson's disease Download PDFInfo
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- JP2023539405A JP2023539405A JP2022578962A JP2022578962A JP2023539405A JP 2023539405 A JP2023539405 A JP 2023539405A JP 2022578962 A JP2022578962 A JP 2022578962A JP 2022578962 A JP2022578962 A JP 2022578962A JP 2023539405 A JP2023539405 A JP 2023539405A
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- azelastine
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- methylcobalamin
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩およびメチルコバラミンを含む医薬組成物が開示されている。アルツハイマー病またはパーキンソン病を有する患者を処置するための医薬組成物の使用方法もまた開示されている。A pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine and methylcobalamin is disclosed. Also disclosed are methods of using the pharmaceutical compositions to treat patients with Alzheimer's disease or Parkinson's disease.
Description
関連出願の相互参照
[001] 本願は、２０１９年４月１２日に出願された米国特許出願第１６／３８２，８８５号の一部継続出願であり、前記特許出願の開示は、参照によってその全体が本明細書に組み込まれる。
Cross-reference of related applications
[001] This application is a continuation-in-part of U.S. Patent Application No. 16/382,885, filed April 12, 2019, the disclosure of which is incorporated herein by reference in its entirety. Incorporated.
技術分野
[002] 本発明は、実用的医薬の分野に、すなわち、アルツハイマー病およびパーキンソン病を処置するための医薬組成物の使用に関する。さらに具体的には、本発明は、アルツハイマー病（AD）およびパーキンソン病（PD）を効果的に処置し得る化合物の新規な組み合わせに関する。
Technical field
[002] The present invention relates to the field of practical medicine, namely the use of pharmaceutical compositions to treat Alzheimer's disease and Parkinson's disease. More specifically, the present invention relates to novel combinations of compounds that can effectively treat Alzheimer's disease (AD) and Parkinson's disease (PD).
[003] アルツハイマー病（AD）は、通常はゆっくりと始まり、時間とともに徐々に悪化する、進行性の慢性神経変性疾患である。ＡＤは、高齢者の認知症の最も一般的な原因である。認知症は、人の日常生活および活動を妨げる程度までの、認知機能、すなわち、思考、記憶、および論理的思考、ならびに行動能力の低下である。ＡＤの初期段階では記憶の低下は穏やかであるが、後期段階のＡＤでは、個体は、会話を継続する能力および彼らの環境に反応する能力を失う。処置をしなければ、ＡＤは最終的には死に繋がる。進行のスピードは様々であり得るが、診断後の典型的な余命は３～９年である。 [003] Alzheimer's disease (AD) is a progressive chronic neurodegenerative disease that usually begins slowly and gradually worsens over time. AD is the most common cause of dementia in the elderly. Dementia is a decline in cognitive function, ie, thinking, memory, and reasoning, and the ability to act, to the extent that it interferes with a person's daily life and activities. In the early stages of AD, memory decline is modest, but in later stages of AD, individuals lose the ability to carry on conversations and respond to their environment. Without treatment, AD ultimately leads to death. Although the speed of progression can vary, the typical life expectancy after diagnosis is 3 to 9 years.
[004] 神経病理学的に、ＡＤは、アミロイドベータタンパク質（Aβ）の老人斑の蓄積および高リン酸化型タウタンパク質（p-tau）の神経原線維変化を特徴とする。現在のエビデンスの大部分は、Ａβの蓄積を孤発性ＡＤの重要な第一の原因因子として挙げている。今までのところ、Ａβまたはｐ－ｔａｕの生成の阻害、可溶性Ａβレベルの低減、およびＣＮＳからのＡβまたはｐ－ｔａｕのクリアランスの増強などのメカニズムを含む、Ａβまたはｐ－ｔａｕのレベルを低下させるための全ての有望なアプローチは、それらの臨床試験で望ましい結果を示していない。Ａβに基づく処置の開発は既知のＡβメカニズムから論理的に得られるが、多くの因子が、個別に適用されると、このような処置の有効性を限定し得る。しかし、さらに重要なことには、多くの他の潜在的メカニズムが、ＡＤにおける重要な原因因子となり得る。このような非Ａβメカニズムは、疾患が進行するに従って、さらに大きな役割またはおそらくは相乗的役割を有し得る。したがって、神経保護戦略の並行した適用はＡＤの発病の遅延およびＡＤの進行の減速において重要な役割を有する可能性が高い。 [004] Neuropathologically, AD is characterized by the accumulation of senile plaques of amyloid beta protein (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein (p-tau). Most of the current evidence points to Aβ accumulation as an important primary causative factor in sporadic AD. So far, mechanisms to reduce Aβ or p-tau levels include inhibiting Aβ or p-tau production, reducing soluble Aβ levels, and enhancing clearance of Aβ or p-tau from the CNS. All promising approaches have not shown desirable results in their clinical trials. Although the development of Aβ-based treatments follows logically from known Aβ mechanisms, many factors, when applied individually, can limit the effectiveness of such treatments. More importantly, however, many other potential mechanisms may be important causative factors in AD. Such non-Aβ mechanisms may have an even greater role or perhaps a synergistic role as the disease progresses. Therefore, the parallel application of neuroprotective strategies is likely to have an important role in delaying the onset of AD and slowing down the progression of AD.
[005] ホモシステインは、メチル化反応を含む必須の代謝経路に関与する含硫アミノ酸である。血中ホモシステインの上昇は、遺伝的障害およびビタミンＢ１２欠乏のマーカーである。ホモシステインの上昇は、血管疾患、神経精神病学的障害、脳卒中、サイレント梗塞、および白質病変を含む神経血管の虚血性疾患と関連している。研究によって、ホモシステインは、アミロイドおよびグルタミン酸塩の神経毒性に、そして認知機能障害およびＡＤに結びつけられている。例えば、ホモシステインの上昇は、脳のアミロイド沈着を有するトランスジェニックマウスおいて海馬ニューロンの消失を誘発する。研究によってまた、認知症ではない個体における血漿中ホモシステインレベルとＡＤおよび認知機能との間の関係が実証されている。この関係はホモシステインレベルの正常範囲にわたっている。ホモシステインレベルの低減は高用量のビタミンＢ１２で容易に達成され得、ＡＤにおける最も妥当な疾患修飾介入となり得る。 [005] Homocysteine is a sulfur-containing amino acid that participates in essential metabolic pathways including methylation reactions. Elevated blood homocysteine is a marker of genetic disorders and vitamin B12 deficiency. Elevated homocysteine is associated with neurovascular ischemic diseases, including vascular disease, neuropsychiatric disorders, stroke, silent infarction, and white matter lesions. Research has linked homocysteine to amyloid and glutamate neurotoxicity and to cognitive dysfunction and AD. For example, elevated homocysteine induces loss of hippocampal neurons in transgenic mice with brain amyloid deposits. Studies have also demonstrated a relationship between plasma homocysteine levels and AD and cognitive function in non-demented individuals. This relationship spans the normal range of homocysteine levels. Reducing homocysteine levels can be easily achieved with high doses of vitamin B12 and may be the most plausible disease-modifying intervention in AD.
[006] ４つのビタミンＢ１２ビタマーの２つの活性形態のうちの１つであるメチルコバラミンは、他の類似体と比較して、ニューロンの細胞内小器官による取り込みにおいて最も効果的である。したがって、アゼラスチンと組み合わせたメチルコバラミンは、ＡＤなどの神経障害のためのより良好な処置選択を提供し得る。 [006] Methylcobalamin, one of the two active forms of the four vitamin B12 vitamers, is the most effective at uptake by neuronal organelles compared to other analogs. Therefore, methylcobalamin in combination with azelastine may provide a better treatment option for neurological disorders such as AD.
[007] 他方で、ＡＤに関連する遺伝的、細胞的、および分子的変化は、活性化した免疫プロセスおよび炎症プロセスがこの疾患の一部であるという証拠を裏付けている。また、ＮＳＡＩＤの長期使用の大きな利益が疫学的研究において示された。したがって、ＡＤが部分的に炎症性疾患であること、および炎症の阻害がＡＤの処置の選択肢であることが、一般に認められている。 [007] On the other hand, genetic, cellular, and molecular changes associated with AD support evidence that activated immune and inflammatory processes are part of this disease. Also, significant benefits of long-term use of NSAIDs have been shown in epidemiological studies. Therefore, it is generally accepted that AD is, in part, an inflammatory disease and that inhibition of inflammation is an option for the treatment of AD.
[008] 炎症はＡＤ脳の病理学的に脆弱な領域で明らかに生じており、このことは、局所的な末梢炎症応答の全複雑性を伴っている。抹消では、変性組織と非常に不溶性の異常物質の沈着とが従来の炎症刺激である。同様に、ＡＤ脳では、損傷を受けたニューロンおよび神経突起ならびに非常に不溶性のアミロイドβペプチドの沈着ならびに神経原線維変化が、炎症の明らかな刺激をもたらす。これらの刺激は別々に生じ、微小局在しており、そしてＡＤの早期前臨床段階から末期段階まで存在し、補体、サイトカイン、急性期反応物質、および他の炎症性メディエーターの局所的上方調節もまた別々に生じ、微小局在しており、そして慢性的である。長年にわたる蓄積で、ＡＤの炎症性メカニズムに由来する直接的損傷およびバイスタンダー損傷は、それを生じさせ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高い。したがって、動物モデルおよび臨床研究はこれまでのところ、ＡＤ炎症がＡＤの発症機序に著しく関与していることを強く示唆している。ＡＤの炎症プロセスおよび免疫調節プロセスをさらに良く理解することによって、この破壊的な障害の発症を回復させるまたは遅延させるまたは予防することができる抗炎症アプローチを開発することが可能となる。 [008] Inflammation clearly occurs in pathologically vulnerable areas of the AD brain, with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and deposition of highly insoluble abnormal substances are the traditional inflammatory stimuli. Similarly, in AD brains, damaged neurons and neurites and deposition of highly insoluble amyloid-β peptide and neurofibrillary tangles result in a clear stimulus of inflammation. These stimuli occur separately, are microlocalized, and are present from early preclinical stages to late stages of AD, including local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators. It also occurs separately, is microlocalized, and chronic. With accumulation over many years, direct and bystander damage resulting from the inflammatory mechanisms of AD is likely to significantly exacerbate the highly pathogenic process that gave rise to it. Therefore, animal models and clinical studies so far strongly suggest that AD inflammation is significantly involved in the pathogenesis of AD. A better understanding of the inflammatory and immunomodulatory processes of AD will allow the development of anti-inflammatory approaches that can reverse or delay or prevent the onset of this devastating disorder.
[009] アゼラスチンは、第２世代の抗ヒスタミン剤として薬理学的に分類されており、Ｈ１受容体での比較的選択的な非鎮静性の競合的アンタゴニストである。さらに特有なこととしては、抗ヒスタミン効果およびマスト細胞安定化効果に加えた、アゼラスチンによる炎症性メディエーターの阻害によって、アゼラスチンは、二重の作用を有する新世代の抗炎症薬となっている。Ｈ１受容体へのアゼラスチンの高い親和性に加えて、いくつかの他の炎症およびアレルギーのメディエーターを修飾するその能力が、その作用メカニズムに関与している。インビトロおよびインビボでの研究ならびに臨床試験で、直接的阻害および炎症細胞の安定化という二重の効果が裏付けられている。インビトロでのデータは、Ｈ１受容体へのアゼラスチンの親和性が第１世代のＨ１アンタゴニストであるクロルフェニラミンの親和性の数倍優れていることが推定されることを示している。アゼラスチンは、Ｈ２受容体に対しては弱い親和性しか有していない。マスト細胞からのヒスタミンの放出はまた、電圧依存性Ｌ型カルシウムチャネルの可逆的な阻害によっておそらく阻害される。マスト細胞の脱顆粒の阻害はまた、とりわけロイコトリエンおよ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減少させ得る。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、および血小板活性化因子などの他の炎症メディエーターと直接拮抗する。 [009] Azelastine is pharmacologically classified as a second generation antihistamine and is a relatively selective, non-sedating, competitive antagonist at the H1 receptor. More uniquely, the inhibition of inflammatory mediators by azelastine, in addition to its antihistamine and mast cell stabilizing effects, makes azelastine a new generation of anti-inflammatory drugs with dual action. In addition to azelastine's high affinity for H1 receptors, its ability to modify several other inflammatory and allergic mediators is involved in its mechanism of action. In vitro and in vivo studies and clinical trials support the dual effects of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that the affinity of azelastine for H1 receptors is estimated to be several times superior to that of chlorpheniramine, a first generation H1 antagonist. Azelastine has only a weak affinity for H2 receptors. Histamine release from mast cells is also likely inhibited by reversible inhibition of voltage-gated L-type calcium channels. Inhibition of mast cell degranulation may also reduce the release of other inflammatory mediators, including leukotrienes and interleukin 1β, among others. Azelastine also directly antagonizes other inflammatory mediators such as tumor necrosis factor alpha, leukotrienes, endothelin 1, and platelet activating factor.
[0010] したがって、アゼラスチン（抗炎症活性を有する抗ヒスタミン薬）とメチルコバラミン（神経系におけるミエリン合成、ニューロンの代謝、およびニューロンの再生を維持するための）との固有の組み合わせは、複数の作用メカニズムを介して機能するという点において、ＡＤ患者のための効果的な処置となる可能性がある。 [0010] Therefore, the unique combination of azelastine (an antihistamine with anti-inflammatory activity) and methylcobalamin (to maintain myelin synthesis, neuronal metabolism, and neuronal regeneration in the nervous system) has multiple effects. It has the potential to be an effective treatment for AD patients in that it works through several mechanisms.
[0011] 本発明は、２つの活性な薬学的成分を含む医薬組成物を含む。この医薬組成物は、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩である第１の活性成分、およびメチルコバラミンである第２の活性成分を含む。 [0011] The present invention includes a pharmaceutical composition that includes two active pharmaceutical ingredients. The pharmaceutical composition comprises a first active ingredient that is azelastine or a pharmaceutically acceptable salt of azelastine, and a second active ingredient that is methylcobalamin.
[0012] 本発明の一部の実施形態において、医薬組成物中のアゼラスチンの薬学的に許容可能な塩は、アゼラスチン塩酸塩である。 [0012] In some embodiments of the invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride.
[0013] 本発明の一部の実施形態において、医薬組成物中のアゼラスチン塩酸塩（および／または他のその塩）は約８ｍｇ～約２４ｍｇの量で提供され、メチルコバラミンは約０．５ｍｇ～約５０ｍｇの量で提供される。 [0013] In some embodiments of the invention, azelastine hydrochloride (and/or other salts thereof) in the pharmaceutical composition is provided in an amount of about 8 mg to about 24 mg, and methylcobalamin is provided in an amount of about 0.5 mg to about 24 mg. Provided in an amount of approximately 50 mg.
[0014] 本発明はまた、固体、液体、ゲル、または溶液の形態の、医薬組成物の経口薬学的投与形態を含む。 [0014] The invention also includes oral pharmaceutical dosage forms of pharmaceutical compositions in the form of solids, liquids, gels, or solutions.
[0015] 本発明はさらに、アルツハイマー病またはパーキンソン病を有する患者への経口薬学的投与形態の投与を介する、医薬組成物の経口薬学的投与形態の医学的使用を含む。 [0015] The invention further includes medical uses of oral pharmaceutical dosage forms of pharmaceutical compositions via administration of the oral pharmaceutical dosage forms to patients with Alzheimer's disease or Parkinson's disease.
[0016] 本発明の範囲内には、アルツハイマー病またはパーキンソン病を処置するための、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む組成物の使用が含まれる。 [0016] Within the scope of the invention are azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients for treating Alzheimer's disease or Parkinson's disease. Includes the use of compositions that include excipients.
[0017] 実施形態はさらに、アルツハイマー病またはパーキンソン病を処置するための薬剤の製造のための、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む組成物の使用を含む。 [0017] Embodiments further provide azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable salts for the manufacture of a medicament for treating Alzheimer's disease or Parkinson's disease. Including the use of compositions containing possible excipients.
[0018] 本発明の一部の実施形態において、約８ｍｇ～約２４ｍｇの量のアゼラスチン塩酸塩（および／または他のその塩）ならびに約０．５ｍｇ～約５０ｍｇの量のメチルコバラミンを含有する医薬組成物の経口薬学的投与形態が、アルツハイマー病またはパーキンソン病を有する患者に投与される。 [0018] In some embodiments of the invention, a medicament containing azelastine hydrochloride (and/or other salts thereof) in an amount of about 8 mg to about 24 mg and methylcobalamin in an amount of about 0.5 mg to about 50 mg. An oral pharmaceutical dosage form of the composition is administered to a patient having Alzheimer's disease or Parkinson's disease.
[0019] 本発明の実施形態には、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む医薬組成物を包含する態様１が含まれる。 [0019] Embodiments of the invention include pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients. 1 is included.
[0020] 態様２は、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩が約８ｍｇ～約２４ｍｇの範囲、例えば、約８ｍｇ～約１８ｍｇ、または約１２ｍｇ～約１６ｍｇ、または約１２ｍｇ、または約８ｍｇ～約２４ｍｇ、または約８ｍｇ、または約８ｍｇ～約２２ｍｇ、または約１０ｍｇ～約２０ｍｇ、または約１０ｍｇ～約１６ｍｇ、または約１０ｍｇ～約１２ｍｇ、または約１２ｍｇ～約２０ｍｇ、または約８ｍｇ～約１２ｍｇ、またはこれらの終点のいずれかの間にあるあらゆる範囲の量で医薬組成物中に存在する、態様１の医薬組成物である。 [0020] Aspect 2 is azelastine or a pharmaceutically acceptable salt of azelastine in a range of about 8 mg to about 24 mg, for example, about 8 mg to about 18 mg, or about 12 mg to about 16 mg, or about 12 mg, or about 8 mg to about 24 mg, or about 8 mg, or about 8 mg to about 22 mg, or about 10 mg to about 20 mg, or about 10 mg to about 16 mg, or about 10 mg to about 12 mg, or about 12 mg to about 20 mg, or about 8 mg to about 12 mg, or The pharmaceutical composition of Embodiment 1 is present in the pharmaceutical composition in any range of amounts between any of these endpoints.
[0021] 態様３は、メチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲、例えば、約０．５ｍｇ～約４５ｍｇ、または約０．５ｍｇ～約３５ｍｇ、または約１ｍｇ～約１０ｍｇ、または約０．５ｍｇ～約５ｍｇ、または約０．５ｍｇ～約２０ｍｇ、または最大約２５ｍｇ、または最大約１５ｍｇ、または最大約８ｍｇ、または最大約５ｍｇ、または約５ｍｇ～約１２ｍｇ、または約２ｍｇ～約８ｍｇ、または約１ｍｇ、またはこれらの終点のいずれかの間にあるあらゆる範囲の量で医薬組成物中に存在する、態様１または２の医薬組成物である。 [0021] Aspect 3 provides that methylcobalamin is in a range of about 0.5 mg to about 50 mg, such as about 0.5 mg to about 45 mg, or about 0.5 mg to about 35 mg, or about 1 mg to about 10 mg, or about 0. 5 mg to about 5 mg, or about 0.5 mg to about 20 mg, or up to about 25 mg, or up to about 15 mg, or up to about 8 mg, or up to about 5 mg, or about 5 mg to about 12 mg, or about 2 mg to about 8 mg, or about The pharmaceutical composition of embodiments 1 or 2 is present in the pharmaceutical composition in an amount of 1 mg, or any range between these endpoints.
[0022] 態様４は、メチルコバラミンが約０．５ｍｇ～約１０ｍｇの範囲の量で医薬組成物中に存在する、態様１～３のいずれか一つの医薬組成物である。 [0022] Embodiment 4 is the pharmaceutical composition of any one of embodiments 1-3, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg.
[0023] 態様５は、医薬組成物中に、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩が約８ｍｇ～約２４ｍｇの範囲の量で存在し、かつメチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で存在する、態様１～４のいずれか一つの医薬組成物である。 [0023] Aspect 5 provides that azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg, and methylcobalamin is present in an amount ranging from about 0.5 mg to about 50 mg. The pharmaceutical composition of any one of embodiments 1 to 4, wherein the pharmaceutical composition is present in an amount ranging from 1 to 4.
[0024] 態様６は、アゼラスチンの薬学的に許容可能な塩がアゼラスチン塩酸塩である、態様１～５のいずれか一つの医薬組成物である。 [0024] Embodiment 6 is the pharmaceutical composition of any one of embodiments 1 to 5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.
[0025] 態様７は、メチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で医薬組成物中に存在する、態様１～６のいずれか一つの医薬組成物である。 [0025] Embodiment 7 is the pharmaceutical composition of any one of embodiments 1-6, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg.
[0026] 態様８は、アゼラスチン塩酸塩が約８ｍｇ～約１８ｍｇの範囲の量で存在する、態様１～７のいずれか一つの医薬組成物である。 [0026] Embodiment 8 is the pharmaceutical composition of any one of embodiments 1-7, wherein azelastine hydrochloride is present in an amount ranging from about 8 mg to about 18 mg.
[0027] 態様９は、経口薬学的投与形態として製剤される、態様１～８のいずれか一つの医薬組成物である。 [0027] Embodiment 9 is the pharmaceutical composition of any one of embodiments 1 to 8, formulated as an oral pharmaceutical dosage form.
[0028] 態様１０は、経口薬学的投与形態が固体形態または液体形態である、態様１～９のいずれか一つの医薬組成物である。 [0028] Embodiment 10 is the pharmaceutical composition of any one of embodiments 1 to 9, wherein the oral pharmaceutical dosage form is in solid or liquid form.
[0029] 態様１１は、アゼラスチン塩酸塩が約８ｍｇ～約１２ｍｇの範囲の量で医薬組成物中に存在し、かつメチルコバラミンの量が約１ｍｇ～約５ｍｇの範囲の量で医薬組成物中に存在する、態様１～１０のいずれか一つの医薬組成物である。 [0029] Aspect 11 provides that azelastine hydrochloride is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 12 mg, and the amount of methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 5 mg. A pharmaceutical composition according to any one of embodiments 1 to 10, wherein the pharmaceutical composition is present.
[0030] 態様１２は、アルツハイマー病またはパーキンソン病を有する患者を処置する方法であって、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む有効量の医薬組成物を、患者のアルツハイマー病および／またはパーキンソン病の１つまたは複数の症候を軽減する、低減させる、予防する、および／または無くすために十分な期間にわたり患者に投与することを含む、方法である。 [0030] Aspect 12 is a method of treating a patient with Alzheimer's disease or Parkinson's disease, the method comprising: azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable An effective amount of a pharmaceutical composition comprising excipients is administered to a patient for a sufficient period of time to alleviate, reduce, prevent, and/or eliminate one or more symptoms of Alzheimer's disease and/or Parkinson's disease in the patient. A method comprising administering to a patient.
[0031] 態様１３は、医薬組成物が、１日に１回もしくは２回、または１日に３回、または２日もしくは３日もしくは４日ごとに１回、経口用の固体形態または液体形態で患者に投与される、態様１～１２のいずれか一つの方法である。 [0031] Aspect 13 provides that the pharmaceutical composition is administered in solid or liquid form for oral administration once or twice a day, or three times a day, or once every two or three or four days. The method of any one of embodiments 1 to 12, wherein the method is administered to a patient.
[0032] 態様１４は、アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩が約８ｍｇ～約２４ｍｇの範囲の量で医薬組成物中に存在する、態様１～１３のいずれか一つの方法である。 [0032] Embodiment 14 is the method of any one of Embodiments 1-13, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg.
[0033] 態様１５は、メチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で組成物中に存在する、態様１～１４のいずれか一つの方法である。 [0033] Embodiment 15 is the method of any one of Embodiments 1-14, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 50 mg.
[0034] 態様１６は、医薬組成物が少なくとも６週間の期間にわたり患者に投与される、態様１～１５のいずれか一つの方法である。 [0034] Aspect 16 is the method of any one of Aspects 1-15, wherein the pharmaceutical composition is administered to the patient over a period of at least 6 weeks.
[0035] 態様１７は、メチルコバラミンが約０．５ｍｇ～１０ｍｇの範囲の量で医薬組成物中に存在する、態様１～１６のいずれか一つの方法である。 [0035] Embodiment 17 is the method of any one of Embodiments 1-16, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to 10 mg.
[0036] 態様１８は、メチルコバラミンが約１ｍｇ～約１０ｍｇの範囲の量で医薬組成物中に存在する、態様１～１７のいずれか一つの方法である。 [0036] Embodiment 18 is the method of any one of Embodiments 1-17, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.
[0037] 態様１９は、医薬組成物中に、アゼラスチンの薬学的に許容可能な塩がアゼラスチン塩酸塩であり、約８ｍｇ～約２４ｍｇの範囲の量で存在し、かつメチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で存在する、態様１～１８のいずれか一つの方法である。 [0037] Aspect 19 provides that in the pharmaceutical composition, the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present in an amount ranging from about 8 mg to about 24 mg, and methylcobalamin is about 0.5 mg. 19. The method of any one of embodiments 1-18, wherein the method is present in an amount ranging from about 50 mg.
[0038] 態様２０は、メチルコバラミンが約０．５ｍｇ～約１０ｍｇの範囲の量で組成物中に存在する、態様１～１９のいずれか一つの方法である。 [0038] Embodiment 20 is the method of any one of Embodiments 1-19, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 10 mg.
[0039] 態様２１は、アルツハイマー病またはパーキンソン病を処置するための、態様１～２０のいずれか一つにおいて開示されているアゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む組成物の使用である。 [0039] Aspect 21 provides azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one as disclosed in any one of aspects 1 to 20 for treating Alzheimer's disease or Parkinson's disease. or the use of a composition comprising multiple pharmaceutically acceptable excipients.
[0040] 態様２２は、アルツハイマー病またはパーキンソン病を処置するための薬剤の製造のための、態様１～２０のいずれか一つにおいて開示されているアゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、メチルコバラミン、および１つまたは複数の薬学的に許容可能な賦形剤を含む組成物の使用である。 [0040] Aspect 22 is azelastine or a pharmaceutically acceptable salt of azelastine disclosed in any one of aspects 1 to 20 for the manufacture of a medicament for treating Alzheimer's disease or Parkinson's disease, Use of a composition comprising methylcobalamin and one or more pharmaceutically acceptable excipients.
[0041] 臨床試験を通して、本発明の発明者らは、アゼラスチンおよびメチルコバラミンの塩形態である活性薬を含む経口投与形態を有する医薬組成物がアルツハイマー病またはパーキンソン病の進行を減速させ得るかまたはさらには停止させ得る処置となることを見出した。 [0041] Through clinical trials, the inventors of the present invention have shown that a pharmaceutical composition having an oral dosage form containing active agents that are salt forms of azelastine and methylcobalamin can slow the progression of Alzheimer's disease or Parkinson's disease or Furthermore, it has been found that the treatment can be stopped.
[0042] 以下で提供する詳細な説明は、本実施例を説明することを目的としており、本実施例が構築または利用され得る形態のみを表すことを意図したものではない。この説明は、実施例の機能、ならびに実施例を構築および操作するための工程の順序を記載している。しかし、同一または同等の機能および順序が、異なる実施例によっても達成され得る。 [0042] The detailed description provided below is for the purpose of describing the embodiments and is not intended to represent the only form in which the embodiments may be constructed or utilized. This description describes the functionality of the embodiments and the order of steps for constructing and operating the embodiments. However, the same or equivalent functionality and order may also be achieved by different embodiments.
[0043] 定義
[0044] 本明細書において使用される場合、以下の語および表現は、これらが使用される文脈が別段のことを示している場合を除いて、以下で示す意味を一般に有するものである。
[0043] Definition
[0044] As used herein, the following words and expressions generally have the meanings set forth below, unless the context in which they are used indicates otherwise.
[0045] 本明細書において使用される場合、用語「メチルコバラミン」は、ビタミンＢ１２の一形態であるコバラミン、コメチルコバラミンを指し、また、ＭｅＣｂｌ、メコバラミン、メコバラミナ（mecobalamina）、メコバラミヌム（mecobalaminum）、またはメチルビタミンＢ１２も意味する。 [0045] As used herein, the term "methylcobalamin" refers to cobalamin, comethylcobalamin, which is a form of vitamin B12, and also refers to MeCbl, mecobalamin, mecobalamina, mecobalaminum, It also means methylvitamin B12.
[0046] 本明細書において使用される場合、用語「アゼラスチン」は、アゼラスチン遊離塩基、または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において、アゼラスチンはまた、塩酸塩またはＨＣｌ塩などのあらゆる薬学的に許容可能な塩も含む。好ましくは、本明細書において記載されてい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またはアゼラスチンＨＣｌのような、その塩酸塩の形態である。さらに好ましくは、本明細書において記載されている本発明の任意の実施形態において、固体経口投与形態を含むアゼラスチンの量および投与量の範囲への言及は、アゼラスチン塩酸塩の量および投与量の範囲への言及である。 [0046] As used herein, the term "azelastine" refers to azelastine free base, or 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)- Refers to 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 its hydrochloride form, 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, including solid oral dosage forms, refer to amounts and dosage ranges of azelastine hydrochloride. This is a reference to.
[0047] 本明細書において使用される場合、用語「塩」は、１－ヒドロキシ－２－ナフトエ酸、２，２－ジクロロ酢酸、２－ヒドロキシエタンスルホン酸、２－オキソグルタル酸、４－アセトアミド安息香酸、４－アミノサリチル酸、酢酸、アジピン酸、アスコルビン酸（Ｌ）、アスパラギン酸（Ｌ）、ベンゼンスルホン酸、安息香酸、樟脳酸（＋）、カンファー－１０－スルホン酸（＋）、カプリン酸（デカン酸）、カプロン酸（ヘキサン酸）、カプリル酸（オクタン酸）、炭酸、ケイ皮酸、クエン酸、シクラミン酸、ドデシル硫酸、エタン－１，２－ジスルホン酸、エタンスルホン酸、ギ酸、フマル酸、ガラクタル酸、ゲンチジン酸、グルコヘプトン酸（Ｄ）、グルコン酸（Ｄ）、グルクロン酸（Ｄ）、グルタミン酸、グルタル酸、グリセロリン酸、グリコール酸、馬尿酸、臭化水素酸、塩酸、イソ酪酸、乳酸（ＤＬ）、ラクトビオン酸、ラウリン酸、マレイン酸、リンゴ酸（－Ｌ）、マロン酸、マンデル酸（ＤＬ）、メタンスルホン酸、ナフタレン－１，５－ジスルホン酸、ナフタレン－２－スルホン酸、ニコチン酸、硝酸、オレイン酸、シュウ酸、パルミチン酸、パモ酸、リン酸、プロピオン酸、ピログルタミン酸（－Ｌ）、サリチル酸、セバシン酸、ステアリン酸、コハク酸、硫酸、酒石酸（＋Ｌ）、チオシアン酸、トルエンスルホン酸（ｐ）、ウンデシレン酸からなる酸の群から選択される酸と形成されたアゼラスチンの塩を指す。 [0047] As used herein, the term "salt" refers to 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, Acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid ( decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid , galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotine Acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, Refers to the salt of azelastine formed with an acid selected from the group of acids consisting of toluenesulfonic acid (p), undecylenic acid.
[0048] 本明細書において使用される場合、「処置」は完全な治癒または不完全な治癒を意味するか、あるいは、処置は、根底にある疾患の症候もしくは関連する状態が少なくとも低減するおよび／もしくは遅延すること、および／または、症候の原因となる根底にある細胞的、生理学的、もしくは生化学的原因もしくはメカニズムの１つもしくは複数が低減する、遅延する、および／もしくは無くなることを意味する。低減するまたは遅延するとは、この文脈において使用される場合、未処置の疾患の生理学的状態だけではなく未処置の疾患の分子状態を含む、未処置の疾患の状態との比較を意味すると理解される。 [0048] As used herein, "treatment" means complete cure or incomplete cure, or treatment at least reduces the symptoms of the underlying disease or associated condition and/or or delaying and/or meaning reducing, delaying, and/or eliminating one or more of the underlying cellular, physiological, or biochemical causes or mechanisms responsible for the symptoms. . Reduce or delay when used in this context is understood to mean a comparison with the state of the untreated disease, including the physiological state of the untreated disease as well as the molecular state of the untreated disease. Ru.
[0049] 用語「有効量」は、処置を必要とする哺乳動物に投与された場合に、以下で定義するような、このような処置をもたらすために十分な量を指す。治療有効量は、処置対象の患者、患者の体重および年齢、疾患状態の重症度、投与様式、ならびにこれらに類するものに応じて変化し、これは、当業者によって容易に判定され得る。医薬組成物は、経口投与によって単回投与または複数回投与のいずれかで投与することができる。投与は、カプセル剤、錠剤、ゲル剤、スプレー剤、ドロップ剤、液剤、懸濁剤、シロップ剤、またはこれらに類するものを介し得る。 [0049] The term "effective amount" refers to an amount sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. A therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the disease condition, the mode of administration, and the like, and can be readily determined by one of skill in the art. Pharmaceutical compositions can be administered by oral administration, either in a single dose or in multiple doses. Administration may be via capsules, tablets, gels, sprays, drops, solutions, suspensions, syrups, or the like.
[0050] 定量的測定の文脈において本明細書において使用される用語「約」は、示された量±１０％を意味する。例えば、±１０％範囲では、「約２ｍｇ」は１．８～２．２ｍｇを意味し得る。 [0050] The term "about" as used herein in the context of quantitative measurements means ±10% of the stated amount. For example, in a ±10% range, "about 2 mg" can mean 1.8 to 2.2 mg.
[0051] 医薬組成物は、当技術分野において公知の方法、例えば、Ａｎｓｅｌ’ｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｄｏｓａｇｅ Ｆｏｒｍｓ ａｎｄ Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍｓ Ｔｅｎｔｈ（Loyd Allen、2013による）およびＨａｎｄｂｏｏｋ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｍａｎｕｆａｃｔｕｒｉｎｇ Ｆｏｒｍｕｌａｔｉｏｎｓ（第１～６巻、Sarfaraz K. Niaziによる）を使用して、薬学的使用のために製剤することができる。こうして、活性化合物の組み込み、および制御放出または遅延放出マトリクスを実現することができる。 [0051] Pharmaceutical compositions can be prepared using methods known in the art, such as Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013) and Handbook of Pharma. Ceutical Manufacturing Formulations (Volumes 1-6, Sarfaraz K. Niazi) can be used to formulate for pharmaceutical use. In this way, incorporation of active compounds and controlled or delayed release matrices can be achieved.
[0052] 流体または固体単位投与形態のいずれかを、リン酸二カルシウム、ケイ酸マグネシウムアルミニウム、ステアリン酸マグネシウム、硫酸カルシウム、デンプン、タルク、ラクトース、アカシア、メチルセルロース、および薬学的賦形剤または担体としての機能的に類似の材料などの従来の成分と例えば混合して、経口投与のために容易に調製することができる。持続放出製剤を任意選択により使用することができる。より高齢のまたは思考散乱の対象では、持続放出製剤がさらに好ましい場合がある。カプセル剤は、医薬組成物を不活性の薬学的希釈剤と混合し、この混合物を適切なサイズを有するハードゼラチンカプセルに挿入することによって、製剤することができる。ソフトカプセル剤が望ましければ、許容可能な植物油、石油エーテル、または他の不活性油との医薬組成物のスラリーを、ゼラチンカプセル内に形成することによってカプセル化することができる。 [0052] Either fluid or solid unit dosage forms containing dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and as a pharmaceutical excipient or carrier. can be easily prepared for oral administration, eg, by mixing with conventional ingredients such as functionally similar materials. Sustained release formulations can optionally be used. In older or distracted subjects, extended release formulations may be even more preferred. Capsules can be prepared by mixing the pharmaceutical composition with an inert pharmaceutical diluent and inserting this mixture into hard gelatin capsules of appropriate size. If soft capsules are desired, they can be encapsulated by forming a slurry of the pharmaceutical composition with an acceptable vegetable oil, petroleum ether, or other inert oil into a gelatin capsule.
[0053] 懸濁剤、シロップ剤、およびエリキシル剤を経口投与または流体単位投与形態に使用することができる。油を含む流体調製物を油溶性形態に使用することができる。着香剤、甘味料、および任意の防腐剤と例えば合わせた、とうもろこし油、ピーナッツ油、または花精油などの植物油によって、許容可能な流体調製物が得られる。界面活性剤を水に添加して、流体単位用量投与量のためのシロップを形成することができる。糖、サッカリン、または生物学的甘味料などの許容可能な甘味料、およびエリキシルの形態の着香剤を有する、水アルコール性薬学的調製物を使用することができる。 [0053] Suspensions, syrups, and elixirs can be used for oral administration or fluid unit dosage forms. Oil-containing fluid preparations can be used in oil-soluble forms. Vegetable oils, such as corn oil, peanut oil, or flower essential oil, combined with flavoring agents, sweeteners, and optional preservatives, provide acceptable fluid preparations. Surfactants can be added to water to form syrups for fluid unit dose administration. Hydroalcoholic pharmaceutical preparations can be used having acceptable sweeteners such as sugar, saccharin, or biological sweeteners, and flavoring agents in the form of elixirs.
[0054] 本開示の固体経口投与製剤は、錠剤、カプレット剤、二層錠剤、フィルムコーティングされた錠剤、丸剤、カプセル剤、またはこれらに類するものの形態を意味する。本開示に従った錠剤は、医薬製剤産業において周知の任意の混合技術および錠剤化技術によって調製することができる。一部の実施例において、投与製剤は、それぞれ調製された持続放出部分および即時放出部分を、ロータリー打錠機、射出成形もしくは圧縮成形、または造粒とその後の圧縮に適合したパンチおよびダイによって直接圧縮することによって作り上げられる。 [0054] Solid oral dosage formulations of the present disclosure refer to the form of tablets, caplets, bilayer tablets, film-coated tablets, pills, capsules, or the like. Tablets according to the present disclosure can be prepared by any mixing and tabletting techniques well known in the pharmaceutical formulation industry. In some embodiments, the dosage formulation is prepared by directly molding the sustained release portion and the immediate release portion, respectively, by a rotary tablet press, injection molding or compression molding, or punches and dies adapted for granulation and subsequent compression. Created by compression.
[0055] 本開示に従って提供される医薬組成物は、通常、経口投与される。本開示はしたがって、本明細書において記載されているアゼラスチンおよびメチルコバラミンと、限定はしないが不活性の固体希釈剤および充填剤、無菌水溶液および様々な有機溶媒を含む希釈剤、浸透増強剤、可溶化剤、崩壊剤、潤滑剤、結合剤、流動促進剤、アジュバント、ならびにこれらの組み合わせを含む１つまたは複数の薬学的に許容可能な賦形剤または担体とを含む固体分散を含む、医薬組成物を提供する。このような組成物は、薬学的技術分野において周知の様式で調製される（例えば、Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth（Loyd Allen、2013による）、およびHandbook of Pharmaceutical Manufacturing Formulations（第１～６巻、Sarfaraz K. Niaziによる）を参照されたい）。 [0055] Pharmaceutical compositions provided according to the present disclosure are typically administered orally. The present disclosure therefore describes the combination of azelastine and methylcobalamin described herein with diluents, penetration enhancers, and fillers including, but not limited to, inert solid diluents and fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions comprising solid dispersions with one or more pharmaceutically acceptable excipients or carriers including solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. provide something. Such compositions are prepared in a manner well known in the pharmaceutical arts (e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by Loyd Allen, 2013), and Handbook of Pharmaceutical Manufacturing Formulations (Parts 1 to 1). 6, by Sarfaraz K. Niazi).
[0056] 適切な賦形剤の一部の例が、本明細書において記載されている。医薬組成物が錠剤に製剤される場合、錠剤はコーティングされていなくてもよいか、または、消化管における崩壊および吸着を遅延させて長時間にわたり持続した作用を提供するためのマイクロカプセル化を含む公知の技術によってコーティングされていてもよい。例えば、単独のまたはワックスと組み合わされたモノステアリン酸グリセリルまたはジステアリン酸グリセリルなどの時間遅延材料を利用することができる。 [0056] Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or include microencapsulation to delay disintegration and adsorption in the gastrointestinal tract to provide sustained action over a long period of time. It may be coated by a known technique. For example, time delay materials such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax, can be utilized.
[0057] 実施形態において、医薬組成物は、ａ）アゼラスチンもしくはアゼラスチンＨＣｌ（もしくは他のその塩）約８ｍｇ～２４ｍｇおよびｂ）メチルコバラミン約０．５ｍｇ～５０ｍｇ、またはａ）アゼラスチンもしくはアゼラスチンＨＣｌ（もしくは他のその塩）約８ｍｇ～１８ｍｇおよびｂ）メチルコバラミン約０．５ｍｇ～１０ｍｇ、またはａ）アゼラスチンもしくはアゼラスチンＨＣｌ（もしくは他のその塩）約１２ｍｇ～１６ｍｇおよびｂ）メチルコバラミン約０．５ｍｇ～５ｍｇを含み得る。例えば、組成物は、ａ）アゼラスチンもしくはアゼラスチンＨＣｌ（もしくは他のその塩）約１２ｍｇおよびｂ）メチルコバラミンＨＣｌ約１ｍｇ、またはａ）アゼラスチンもしくはアゼラスチンＨＣｌ（もしくは他のその塩）約８ｍｇ～２４ｍｇおよびｂ）任意の量のメチルコバラミンを含み得る。 [0057] In embodiments, the pharmaceutical composition comprises a) about 8 mg to 24 mg of azelastine or azelastine HCl (or other salt thereof) and b) about 0.5 mg to 50 mg of methylcobalamin, or a) a) azelastine or azelastine HCl (or a) about 8 mg to 18 mg of methylcobalamin, or a) about 12 mg to 16 mg of azelastine or azelastine HCl (or other salt thereof), and b) about 0.5 mg to 5 mg of methylcobalamin. may include. For example, the composition may include a) about 12 mg of azelastine or azelastine HCl (or other salt thereof) and b) about 1 mg of methylcobalamin HCl, or a) about 8 mg to 24 mg of azelastine or azelastine HCl (or other salt thereof) and b) ) may contain any amount of methylcobalamin.
[0058] 実施形態において、医薬組成物は、ａ）約８ｍｇ～約２２ｍｇの範囲、例えば約１０ｍｇ～約２０ｍｇ、もしくは約１０ｍｇ～約１６ｍｇ、もしくは約８ｍｇ～約１８ｍｇ、もしくは約１０ｍｇ～約１２ｍｇ、もしくは約１２ｍｇ～約２０ｍｇ、もしくは約８ｍｇ～約１２ｍｇの範囲の、またはこれらの終点のいずれかの間にあるあらゆる範囲の量のアゼラスチンまたはアゼラスチンＨＣｌ（または他のその塩）、あるいは任意の量のアゼラスチン、アゼラスチンＨＣｌ（または他のその塩）、およびｂ）約０．５ｍｇ～約５０ｍｇの範囲、例えば約０．５ｍｇ～約４５ｍｇ、もしくは約０．５ｍｇ～約３５ｍｇ、もしくは約１ｍｇ～約１０ｍｇ、もしくは約０．５ｍｇ～約５ｍｇ、もしくは約０．５ｍｇ～約２０ｍｇ、もしくは最大約２５ｍｇ、もしくは最大約１５ｍｇ、もしくは最大約８ｍｇ、もしくは最大約５ｍｇ、もしくは約５ｍｇ～約１２ｍｇ、もしくは約２ｍｇ～約８ｍｇ、もしくは約１ｍｇの範囲、またはこれらの終点のいずれかの間にあるあらゆる範囲の量のメチルコバラミンを含み得る。 [0058] In embodiments, the pharmaceutical composition comprises: a) in the range of about 8 mg to about 22 mg, such as about 10 mg to about 20 mg, or about 10 mg to about 16 mg, or about 8 mg to about 18 mg, or about 10 mg to about 12 mg; or azelastine or azelastine HCl (or other salt thereof) in an amount ranging from about 12 mg to about 20 mg, or from about 8 mg to about 12 mg, or any range between either of these endpoints, or any amount of azelastine or azelastine HCl (or other salt thereof). azelastine, azelastine HCl (or other salt thereof), and b) in the range of about 0.5 mg to about 50 mg, such as about 0.5 mg to about 45 mg, or about 0.5 mg to about 35 mg, or about 1 mg to about 10 mg, or about 0.5 mg to about 5 mg, or about 0.5 mg to about 20 mg, or up to about 25 mg, or up to about 15 mg, or up to about 8 mg, or up to about 5 mg, or about 5 mg to about 12 mg, or about 2 mg to about It may contain methylcobalamin in amounts ranging from 8 mg, or about 1 mg, or any range between any of these endpoints.
[0059] 実施形態において、組成物中に存在するアゼラスチンまたはアゼラスチンＨＣｌ（または他のその塩）の量は、組成物中に存在するメチルコバラミンの量に等しいか、それより多いか、またはそれより少なくてよい。実施形態において、上記で開示したまたは特許請求の範囲に記載の量のいずれかを使用して、組成物中に存在するアゼラスチンまたはアゼラスチンＨＣｌ（および／または他のその塩）の量は、組成物中に存在するメチルコバラミンの量の２倍、または３倍、または４、５、６、７、８、９、１０、１５、２０、２５、３０、３５、４０、４５、５０、７５、もしくは１００倍であり得るか、あるいは逆の場合も同様であり得る。本発明の組成物のいずれか１つまたは複数は、本明細書において開示されている発明の方法のいずれか１つもしくは複数、または他の組成物使用方法と共に使用することができる。 [0059] In embodiments, the amount of azelastine or azelastine HCl (or other salt thereof) present in the composition is equal to, greater than, or greater than the amount of methylcobalamin present in the composition. Less is better. In embodiments, the amount of azelastine or azelastine HCl (and/or other salts thereof) present in the composition, using any of the amounts disclosed above or claimed, or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or It can be 100x or vice versa. Any one or more of the compositions of the invention can be used with any one or more of the inventive methods disclosed herein or other methods of using the compositions.
[0060] 実際に投与される、アゼラスチンＨＣｌおよびメチルコバラミンを含む医薬組成物の量は通常、処置対象の状態、選択された投与経路、投与される実際の化合物およびその相対的活性、個々の患者の年齢、体重、および応答、患者の症候の重症度、ならびにこれらに類するものを含む、関連する状況に照らして、医師によって決定される。 [0060] The actual amount of a pharmaceutical composition comprising azelastine HCl and methylcobalamin administered will typically depend on the condition being treated, the route of administration chosen, the actual compound administered and its relative activity, and the individual patient. determined by the physician in the light of relevant circumstances, including the age, weight, and response of the patient, the severity of the patient's symptoms, and the like.
[0061] 本明細書において記載されているアゼラスチンＨＣｌおよびメチルコバラミンを含有する医薬組成物、薬学的投与形態、および錠剤は、アルツハイマー病またはパーキンソン病を有する患者に、１日に１回、１日に２回、１日に３回、１日に４回、２日に１回、週に１回、週に２回、週に３回、週に４回、もしくは週に５回、またはこれらの組み合わせで、経口投与によって投与される。当業者には、上記で開示したまたは特許請求の範囲において記載されている組成物中のアゼラスチンおよびメチルコバラミンの量が代わりに１日投与量となり得、またむしろ、適宜、単回用量に製剤され得ることが理解される。 [0061] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing azelastine HCl and methylcobalamin described herein can be administered once daily to patients with Alzheimer's disease or Parkinson's disease. twice a week, three times a day, four times a day, once every two days, once a week, twice a week, three times a week, four times a week, or five times a week, or in combination, administered by oral administration. It will be appreciated by those skilled in the art that the amounts of azelastine and methylcobalamin in the compositions disclosed above or in the claims could alternatively be a daily dose, or, rather, formulated into a single dose as appropriate. It is understood that you will get.
[0062] 実施形態において、患者は、８ｍｇ～約２４ｍｇの範囲のアゼラスチンＨＣｌおよび約０．５ｍｇ～約５０ｍｇの範囲の量のメチルコバラミンからなる治療上有効な１日投与量を有する医薬組成物を投与される。 [0062] In embodiments, the patient receives a pharmaceutical composition having a therapeutically effective daily dosage consisting of azelastine HCl in the range of 8 mg to about 24 mg and methylcobalamin in an amount ranging from about 0.5 mg to about 50 mg. administered.
[0063] 実施形態において、本明細書において記載されているアゼラスチンまたはアゼラスチンＨＣｌ（または他のその塩）およびメチルコバラミンを含有する医薬組成物の薬学的投与形態および錠剤は、約２～１６週間で、例えば２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、または１６週間以内で、またはこれらの間の任意の範囲で、アルツハイマー病またはパーキンソン病の進行の減速または症候の回復において有効である。ＡＤまたはＰＤを有する患者でミニメンタルステート検査（MMSE）および日常生活動作（ADL）が評価される場合、ＭＭＳＥおよびＡＤＬのスコアは５０％超改善され得る。 [0063] In embodiments, pharmaceutical dosage forms and tablets of pharmaceutical compositions containing azelastine or azelastine HCl (or other salts thereof) and methylcobalamin described herein are administered in about 2 to 16 weeks. , for example, within 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks, or any range therebetween, Alzheimer's disease or Parkinson's disease. It is effective in slowing down the progression of the disease or reversing symptoms. When the Mini-Mental State Examination (MMSE) and activities of daily living (ADL) are assessed in patients with AD or PD, the MMSE and ADL scores can be improved by more than 50%.
[0064] 以下の実施例は例示的なものであり、特許請求の範囲に記載の発明の対象の範囲を限定するものと解釈されるべきではない。
[0065]
[0064] The following examples are illustrative and should not be construed as limiting the scope of claimed subject matter.
[0065]
[0066] 中期アルツハイマー病（AD）を２年間有しており、処置前のベースラインＭＭＳＥスコアが１２であり、そして日常生活動作スコアのバーセルインデックス（BI）が３０の、７０歳の患者を、メチルコバラミンおよびアゼラスチンからなる医薬組成物、例えば、メチルコバラミンを１．０ｍｇの量で含み、アゼラスチン、アゼラスチンＨＣｌ、または他のその塩を８ｍｇの量で含む組成物で、最大１日に２回、処置することができる（または、上記のもしくは特許請求の範囲に記載の組成物のいずれか、または上記のまたは特許請求の範囲に記載の任意の処置プロトコルまたは時間で）。２週間後、３週間後、４週間後、５週間後、６週間後、７週間後、８週間後、またはそれ以降、当該患者のＡＤ症候の１つまたは複数は、少なくとも１０％、２０％、３０％、４０％、５０％、６０％、７０％、８０％、９０％、１００％、またはそれを超えて改善すると予想される。例えば、当該患者のＭＭＳＥスコアは１２から少なくとも２２まで改善すると予想され、これは８３％の改善であり、また、当該患者のＢＩスコアは３０から少なくとも８０まで改善すると予想され、これは１６７％の改善である。この組成物によるこの劇的な臨床結果はＡＤ患者では予想外であり、アゼラスチン単独を摂取した場合よりも優れている。アゼラスチンは、ミクログリアの活性化の低下、サイトカイン発現の阻害、活性酸素種への対抗、および炎症プロセスにおける核因子カッパＢの役割の抑制によって、ＡＤの炎症プロセスを低減させて、ＡＤにおける神経変性を減速させ、さらには停止させ得る。しかし、ミエリン合成、神経の代謝、およびニューロンの再生を促すことによって神経細胞の成長を促進するメチルコバラミンは、アゼラスチンと組み合わせると、アゼラスチンの効果を維持し、ＡＤ患者の症候の回復を増大させ、こうしてこの組成物は、ＡＤ患者のためのより効果的で持続した処置をもたらす。 [0066] A 70-year-old patient with intermediate Alzheimer's disease (AD) for 2 years, with a pre-treatment baseline MMSE score of 12, and a Barthel Index (BI) of activities of daily living score of 30, was a pharmaceutical composition consisting of methylcobalamin and azelastine, e.g., a composition comprising methylcobalamin in an amount of 1.0 mg and azelastine, azelastine HCl, or other salt thereof in an amount of 8 mg, up to twice a day; (or with any of the above or claimed compositions, or any of the above or claimed treatment protocols or times). After 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or later, one or more of the patient's AD symptoms is at least 10%, 20% , 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, the patient's MMSE score is expected to improve from 12 to at least 22, which is an 83% improvement, and the patient's BI score is expected to improve from 30 to at least 80, which is a 167% improvement. It's an improvement. This dramatic clinical result with this composition is unexpected in AD patients and is superior to taking azelastine alone. Azelastine reduces the inflammatory process in AD and inhibits neurodegeneration in AD by reducing microglial activation, inhibiting cytokine expression, counteracting reactive oxygen species, and suppressing the role of nuclear factor kappa B in the inflammatory process. It can be slowed down and even stopped. However, methylcobalamin, which promotes neuronal growth by promoting myelin synthesis, neuronal metabolism, and neuronal regeneration, maintains the efficacy of azelastine and increases symptom recovery in AD patients when combined with azelastine. This composition thus provides a more effective and sustained treatment for AD patients.
[0067] パーキンソン病（PD）を３年間有しており、処置前のベースライン統一パーキンソン病評価スケール（UPDRS）のトータルスコアが９０である、７０歳の患者を、メチルコバラミンおよびアゼラスチンからなる医薬組成物、例えば、メチルコバラミンを１．０ｍｇの量で含み、アゼラスチン、アゼラスチンＨＣｌ、または他のその塩を８ｍｇの量で含む組成物で、最大１日に２回、処置することができる（または、上記のもしくは特許請求の範囲に記載の組成物のいずれか、または上記のもしくは特許請求の範囲に記載の任意の処置プロトコルもしくは時間で）。２週間後、３週間後、４週間後、５週間後、６週間後、７週間後、８週間後、またはそれ以降、当該患者のＰＤ症候の１つまたは複数は、少なくとも１０％、２０％、３０％、４０％、５０％、６０％、７０％、８０％、９０％、１００％、またはそれを超えて改善すると予想される。例えば、当該患者のＵＰＤＲＳトータルスコアは９０から少なくとも４０まで改善すると予想され、これは５６％の改善である。加えて、患者のＭＭＳＥスコアが評価される場合、これは５０％超改善すると予想される。 [0067] A 70-year-old patient with Parkinson's disease (PD) for 3 years and a pre-treatment baseline Unified Parkinson's Disease Rating Scale (UPDRS) total score of 90 was treated with a pharmaceutical composition consisting of methylcobalamin and azelastine. up to twice a day (or any of the above or claimed compositions, or any of the above or claimed treatment protocols or times). After 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or later, one or more of the patient's PD symptoms is at least 10%, 20% , 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, the patient's UPDRS total score is expected to improve from 90 to at least 40, which is a 56% improvement. Additionally, if the patient's MMSE score is evaluated, this is expected to improve by more than 50%.
[0068] 参考文献
[0069] U.S. Patent Nos. 9,919,050 (Mar. 20, 2018, Dang, et al); 9,901,585 (Feb. 27, 2018, Lulla, et al); 8,859,531 (Oct. 14, 2014, Lee, et al); 8,758,816 (June 24, 2014, Fuge, et al); 8,318,709 (Nov. 27, 2012, Lulla, et al); 8,304,405 (Nov. 6, 2012, Lulla, et al); 8,168,620 (May 1, 2012, Lulla, et al); 8,071,073 (Dec. 6, 2011, Dang, et al); 7,022,687 (Apr. 4, 2006, Szelenyl, et al); 6,017,909 (Jan. 25, 2000, Hettche, et al); 5,994,357 (Nov. 30, 1999, Theoharides); 5,086,050 (Feb. 4, 1992, Hettche, et al); and 5,068,233 (Nov. 26, 1991, Achterrath-Tuckerman, et al.); 8,741,319 (June 3, 2014, Crain et al); and U.S. Published Application Nos. 2010/0168053 (Kurtz); 2009/0012039 (Kurtz); and 2014/0127328 (Crain et al).
[0070] Carlos Alberto Calderon-Ospina, Mauricio Orlando Nava, 2020. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther. 2020; 26:5-13.
[0071] Katsushi, Koyoma et al. 2002. Efficacy of Methylcobalamin on Lowing Total Homocysteine Plasma Concentrations in Haemodialysis Patients Receiving High-dose Folic Acid Supplementation. Nephrol Dial Transplant, 2002, 16: 911-22.
[0072] Yiting Zhang, et al. 2016. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLOS ONE, 0146797 January 22, 2016.
[0073] Theresa Kobe, et al. 2016. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. American Journal of Clinical. Nutrition, 2016; 103:1045-54.
[0074] Michael Leon, Darrell Sawmiller, R. Douglas Shytle, and Jun Tan, 2018. Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer’s Disease. Cell Med. 2018; 10: 2155179017722280.
[0075] Paul S. Aisen, et al. 2008. High Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer’s Disease: A Randomized Controlled Trial. JAMA. 2008 October 15; 300(15): 1774-1783.
[0076] A. David Smith, et al, 2010. Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS ONE, September 2010, Volume 5, Issue 9, e12244.
[0077] Uwe Grober, Klaus Kisters and Joachim Schmidt, 2013. Neuroenhancement with Vitamin B12-Underestimated Neurological Significance. Nutrients, 2013, 5, 5031-5045.
[0078] Gupta JK and Qureshi Shaiba Sana, 2015. Potential Benefits of Methylcobalamin: Austin J. Pharmacol. Ther. Volume 3, Issue 3, 2015.
[0079] Patricia B Williams, Elizabeth Crandall and John D Sheppard, 2010, Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clinical Ophthalmology, 2010:4 993-1001.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999; 36:329-352.
[0086] Aiko Hatakeyama, et al, 2008, Azelastine hydrochloride on behavioral and psychological symptoms and activities of daily living in dementia patients. Geriatr Gerontol Int 2008; 8: 59-61.
[0087] Duraisamy Kempuraj, et al. 2003, Azelastine Inhibits Secretion of IL-6, TNF-alpha and IL-8 as Well as NF-kappaB Activation and Intracellular Calcium Ion Levels in Normal Human Mast Cells. Int Arch Allergy Immunol. 132 (3), 231-9 Nov 2003.
[0088] Kazunori Yoneda, et al. 1997, Suppression by Azelastine Hydrochloride of NF-KB Activation Involved in Generation of Cytokines and Nitric Oxide. Japanese Journal of Pharmacology, 73: 145-53.
[0089] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013).
[0090] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.
[0068] References
[0069] US Patent Nos. 9,919,050 (Mar. 20, 2018, Dang, et al); 9,901,585 (Feb. 27, 2018, Lulla, et al); 8,859,531 (Oct. 14, 2014, Lee, et al); 8,758,816 (June 24, 2014, Fuge, et al); 8,318,709 (Nov. 27, 2012, Lulla, et al); 8,304,405 (Nov. 6, 2012, Lulla, et al); 8,168,620 (May 1, 2012, Lulla, et al) al); 8,071,073 (Dec. 6, 2011, Dang, et al); 7,022,687 (Apr. 4, 2006, Szelenyl, et al); 6,017,909 (Jan. 25, 2000, Hettche, et al); 5,994,357 (Nov. 30 , 1999, Theoharides); 5,086,050 (Feb. 4, 1992, Hettche, et al); and 5,068,233 (Nov. 26, 1991, Achterrath-Tuckerman, et al.); 8,741,319 (June 3, 2014, Crain et al); and US Published Application Nos. 2010/0168053 (Kurtz); 2009/0012039 (Kurtz); and 2014/0127328 (Crain et al).
[0070] Carlos Alberto Calderon-Ospina, Mauricio Orlando Nava, 2020. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther. 2020; 26:5- 13.
[0071] Katsushi, Koyoma et al. 2002. Efficacy of Methylcobalamin on Lowing Total Homocysteine Plasma Concentrations in Haemodialysis Patients Receiving High-dose Folic Acid Supplementation. Nephrol Dial Transplant, 2002, 16: 911-22.
[0072] Yiting Zhang, et al. 2016. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLOS ONE, 0146797 January 22, 2016.
[0073] Theresa Kobe, et al. 2016. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. American Journal of Clinical. Nutrition, 2016; 103:1045-54.
[0074] Michael Leon, Darrell Sawmiller, R. Douglas Shytle, and Jun Tan, 2018. Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer's Disease. Cell Med. 2018; 10: 2155179017722280.
[0075] Paul S. Aisen, et al. 2008. High Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer's Disease: A Randomized Controlled Trial. JAMA. 2008 October 15; 300(15): 1774-1783.
[0076] A. David Smith, et al, 2010. Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS ONE, September 2010, Volume 5, Issue 9, e12244.
[0077] Uwe Grober, Klaus Kisters and Joachim Schmidt, 2013. Neuroenhancement with Vitamin B12-Underestimated Neurological Significance. Nutrients, 2013, 5, 5031-5045.
[0078] Gupta JK and Qureshi Shaiba Sana, 2015. Potential Benefits of Methylcobalamin: Austin J. Pharmacol. Ther. Volume 3, Issue 3, 2015.
[0079] Patricia B Williams, Elizabeth Crandall and John D Sheppard, 2010, Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clinical Ophthalmology, 2010:4 993-1001.
[0080] 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.
[0081] 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 .
[0082] 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.
[0083] 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.
[0084] 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.
[0085] Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999; 36:329-352.
[0086] Aiko Hatakeyama, et al, 2008, Azelastine hydrochloride on behavioral and psychological symptoms and activities of daily living in dementia patients. Geriatr Gerontol Int 2008; 8: 59-61.
[0087] Duraisamy Kempuraj, et al. 2003, Azelastine Inhibits Secretion of IL-6, TNF-alpha and IL-8 as Well as NF-kappaB Activation and Intracellular Calcium Ion Levels in Normal Human Mast Cells. Int Arch Allergy Immunol. 132 (3), 231-9 Nov 2003.
[0088] Kazunori Yoneda, et al. 1997, Suppression by Azelastine Hydrochloride of NF-KB Activation Involved in Generation of Cytokines and Nitric Oxide. Japanese Journal of Pharmacology, 73: 145-53.
[0089] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013).
[0090] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.
[0091] 本発明を、様々な特徴を有する特定の実施形態を参照して記載してきた。上記で提供した開示に照らして、当業者には、様々な修正および変更が、本発明の範囲または趣旨から逸脱することなく、本発明の実施で行われ得ることが明らかとなろう。当業者には、開示された特徴が単独で使用され得るか、任意の組み合わせで使用され得るか、または所与の適用もしくは設計の要件および仕様に基づいて省略され得ることが認識されよう。実施形態がある特定の特徴を「含む」と記載されている場合、実施形態が代わりに特徴のいずれか１つまたは複数「からなる」または「から基本的になる」場合もあることが理解される。本明細書において開示されている方法のいずれも、本明細書において開示されている組成物のいずれかとまたはあらゆる他の組成物と共に使用することができる。同様に、開示されている組成物のいずれも、本明細書において開示されている方法のいずれかとまたはあらゆる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、本発明の明細書および実施を考慮することで当業者に明らかとなろう。 [0091] The invention has been described with reference to specific embodiments having various features. In light of the disclosure provided above, it will be apparent to those skilled in the art that various modifications and changes 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 alone, in any combination, or omitted based on the requirements and specifications of a given application or design. Where an embodiment is described 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. Ru. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Similarly, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.
[0092] 値の範囲が本明細書において示されている場合、その範囲の上限と下限との間の各値もまた具体的に開示されていることに特に留意されたい。これらのより小さな範囲の上限および下限は、独立してこの範囲内に含まれてもこの範囲から除外されてもよい。単数形「ａ」、「ａｎ」、および「ｔｈｅ」は、文脈から別段のことが明らかに示されない限り、複数形の言及を含む。明細書および実施例は典型的な性質であると考えられるものであり、また、本発明の本質から逸脱しない変更は本発明の範囲内に含まれるものである。さらに、本開示において引用されている参考文献の全ては、それぞれが個別に参照によってその全体が本明細書に組み込まれ、したがって、本発明の実施可能な程度の開示を効率的に補足するためのものであり、また、当業者のレベルを詳述する背景技術を示すためのものである。
[0092] It is specifically noted that when a range of values is expressed herein, each value between the upper and lower limits of the range is also specifically disclosed. The upper and lower limits of these smaller ranges may independently be included in or excluded from the range. The singular forms "a,""an," and "the" include plural references unless the context clearly dictates otherwise. The specification and examples are considered to be typical in nature, and modifications that do not depart from the essence of the invention are intended to be included within its scope. Additionally, all of the references cited in this disclosure are each individually incorporated by reference in its entirety, and are therefore incorporated by reference in its entirety to effectively supplement the enabling disclosure of the present invention. It is intended to provide background information that is detailed to the level of those skilled in the art.
Claims (22)
メチルコバラミン、
および１つまたは複数の薬学的に許容可能な賦形剤
を含む、医薬組成物。 azelastine or a pharmaceutically acceptable salt of azelastine,
methylcobalamin,
and one or more pharmaceutically acceptable excipients.
メチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で医薬組成物中に存在する、
請求項１に記載の医薬組成物。 azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg, and methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. exists in
The pharmaceutical composition according to claim 1.
アゼラスチンまたはアゼラスチンの薬学的に許容可能な塩、
メチルコバラミン、
および１つまたは複数の薬学的に許容可能な賦形剤
を含む有効量の医薬組成物を、
患者のアルツハイマー病またはパーキンソン病の１つまたは複数の症候を軽減する、低減させる、予防する、および／または無くすために十分な期間にわたり患者に投与する工程
を含む方法。 A method of treating a patient with Alzheimer's disease or Parkinson's disease, the method comprising:
azelastine or a pharmaceutically acceptable salt of azelastine,
methylcobalamin,
and an effective amount of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients,
A method comprising administering to a patient for a sufficient period of time to alleviate, reduce, prevent, and/or eliminate one or more symptoms of Alzheimer's disease or Parkinson's disease in the patient.
メチルコバラミンが約０．５ｍｇ～約５０ｍｇの範囲の量で医薬組成物中に存在する、
請求項１２に記載の方法。 A pharmaceutically acceptable salt of azelastine is azelastine hydrochloride, which is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg, and methylcobalamin is present in an amount ranging from about 0.5 mg to about 50 mg. present in the pharmaceutical composition,
13. The method according to claim 12.
A composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients for the manufacture of a medicament for treating Alzheimer's disease or Parkinson's disease. use of things.
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2020
- 2020-06-26 CA CA3183560A patent/CA3183560A1/en active Pending
- 2020-06-26 WO PCT/US2020/039916 patent/WO2021262196A1/en unknown
- 2020-06-26 JP JP2022578962A patent/JP2023539405A/en active Pending
- 2020-06-26 EP EP20942038.9A patent/EP4171539A4/en active Pending
- 2020-06-26 CN CN202080102343.2A patent/CN115776885A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP4171539A1 (en) | 2023-05-03 |
| WO2021262196A1 (en) | 2021-12-30 |
| CA3183560A1 (en) | 2021-12-30 |
| CN115776885A (en) | 2023-03-10 |
| EP4171539A4 (en) | 2024-01-17 |
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