JP6280535B2 - S−アデノシルメチオニンおよび没食子酸エステルを含む組成物 - Google Patents
S−アデノシルメチオニンおよび没食子酸エステルを含む組成物 Download PDFInfo
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- JP6280535B2 JP6280535B2 JP2015238622A JP2015238622A JP6280535B2 JP 6280535 B2 JP6280535 B2 JP 6280535B2 JP 2015238622 A JP2015238622 A JP 2015238622A JP 2015238622 A JP2015238622 A JP 2015238622A JP 6280535 B2 JP6280535 B2 JP 6280535B2
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Description
本出願は、2012年10月17日に提出した米国仮出願第61/715,138号に基づく利益を享受するものであり、該仮出願は、参照によりその全体が本明細書中に取り込まれるものとする。
錠剤などの製剤を生成するための処理方法および/またはパラメータに起因する、製品または剤形の特性には、限定するものではないが、硬度、厚さ、含水量、破砕性、崩壊度、溶解特性、形状、大きさ、重量、均質性および組成が含まれる。これらの製品の特性は、多くの方法で調節でき、最終的なインビトロおよび/またはインビボでの製剤の働きに影響を与える。一例として、圧縮または成形過程により生成される錠剤は、それらが作られる製造パラメータにより、いろいろな厚みまたは硬度を有していても良い。製品または剤形特性は、適用される賦形剤の選択、賦形剤組成物、製造方法の結果であっても良く、またはこれらの組み合わせであって良い。賦形剤の組み合わせ、また最終剤形の製品の特性(処理方法または処理パラメータを含む)は、インビボでの活性成分の薬物動態学的特性を最終的に決定するであろう。本発明のSAMe製剤は、例えば、混合方法(ふるいの大きさ、回転数、および製粉を含む)乾燥時間、圧縮条件、環境パラメータ(例えば、温度および湿度)およびこれらの組み合わせなどの特定の状況下で処理または製造しても良い。錠剤同士を定量的に比較するためには、いくつかのこれらの製品または剤形の特性を測定することが通例である。これは、複数のバッチの複製を試みる際にも必要である。
崩壊剤は、非経口ではない製剤に添加され、薬の放出を助ける液体と接触した場合に、製品または剤形(つまり、錠剤またはカプセル)の崩壊を誘導する。崩壊剤の添加の目的は、製品の断片の表面積を大きくし、これらの分子を製剤の形態に保つ凝集力を克服することである。これは、剤形が水分を含んで膨張することを促進されることにより行われ、胃腸管で分解される。デンプンおよびセルロースなどのいくつかの結合剤もまた崩壊剤として機能する。他の崩壊剤は、粘土、セルロース誘導体、アルギン、ガムおよび架橋したポリマーである。「超崩壊剤(super-disintegrant)」と呼ばれる崩壊剤の別の群は、しばしば利用される。これらの材料は、低(2〜5%)濃度で有効である。本発明に使用される適切であり得る「超崩壊剤(super-disintegrant)」には、限定するものではないが、デンプングリコール酸ナトリウム(SSG)、クロスカルメロースナトリウムまたはクロスポビドンが含まれる。
製品の原体を1つに結びつけ、製品を所望の形に維持するのに役立つ結合剤料は、「結合剤」または「造粒剤」として知られる。本発明に使用する適切な結合剤は、限定するものではないが、糖、ゼラチン、ガム、結晶セルロースおよび変性セルロース、ワックスまたは合成ポリマー状のポリエチレングリコールまたはポリビニルピロリドンに例示される。いくつかの実施形態は、SAMeおよび1以上の没食子酸エステルに加えて1以上の結合剤を含む改善された薬物動態学的組成物を含んでも良い。
製品製剤でしばしば利用される追加の賦形剤は、潤滑剤である。これらは、製品の凝集を最小限にし、また、製造機械からの剥離を促し、製造過程で助けとなる物質である。経口製剤に使用される最も一般的な「潤滑剤」は、テアリン酸マグネシウムである;しかしながら、別の一般的に使用される製品潤滑剤には、タルク、ステアリン酸カルシウム、ステアリン酸(ステアリン)、硬化植物油、安息香酸ナトリウム、ロイシン、carbowax4000およびフマル酸ステアリルナトリウムが含まれ、これら全ては、適切な本発明の使用に適切であってもよい。さらなる例示的な実施形態もまたSAMeおよび1以上の没食子酸エステルおよび1以上の潤滑剤を含む改善された薬物動態学的組成物に関する。
流動促進剤は、「流動助剤」とも呼ばれ、製品が作られるとき、製品の流動性を形成している粉末を保つ助けとなり、塊になるのを防いでいる。一般的に使用される流動促進剤で、本発明の使用に適切であってもよいものの例としては、コロイド状二酸化ケイ素、タルク、ケイ酸カルシウムおよびケイ酸マグネシウムが含まれる。更なる実施形態は、SAMeおよび1以上の没食子酸エステルを含む組成物および1以上の改善された薬物動態学的流動促進剤に関する。
薬物動態学的特性を改善するために修正されても良い、および/またはSAMe−没食子酸エステル製剤の溶解プロファイルを変化させる処理方法および/またはパラメータには、限定するものではないが、以下のものが含まれる:相対湿度、温度、乾燥時間および他の環境パラメータである。
没食子酸プロピルは、外部から投与されたSAMeの血漿レベルを著しく増加させる
没食子酸メチル、没食子酸エチル、没食子酸ブチル、没食子酸イソブチル、没食子酸イソアミルまたは没食子酸オクチルのいずれかとSAMeを混合させ、SAMeおよび異なる化学構造のさまざまな没食子酸アルキルを含む錠剤を生成した(以下の構造を参照)。そして、錠剤をビーグル犬に投与し、やがて血液試料を取り出した。血漿中のSAMeの濃度分析を使用し、経口投与されたSAMeが血液中へ摂取される際のこれらの没食子酸エステルの効果を比較した。
没食子酸関連分子の存在下におけるビーグル血漿のSAMe値
没食子酸プロピルと構造的に類似であることがよく知られる薬剤、ブチル化ヒドロキシトルエン(BHT)、プロピルパラベンまたは没食子酸、を含むSAMe組成物を使って実施例1で行ったのと同様のインビボ実験を行った。BHT、プロピルパラベンおよび没食子酸プロピルは、しばしば組み合わせて使用される食品向けの抗酸化剤である。これらの薬剤は、以下に示すものと構造的に類似である:
Caco−2細胞輸送でのSAMe摂取における没食子酸プロピル投与の効果
没食子酸プロピルで処理をしたCaco−2細胞の単層膜のSAMeの透過性に関するインビトロの実験を行い、処理していないCaco−2細胞の単層膜と比較して、Caco−2細胞により吸収されるSAMeの量を増加させる没食子酸プロピルの値を特定した。Caco−2細胞株は、ヒトの結腸直腸がんに由来し、胃腸薬の吸収の研究のためにインビトロの細胞培養のモデルに広く用いられている(Stewart, B., (1995) Pharm. Res. 12:693)。これらのモデルにおいて、純粋な細胞株は、半透過性膜上に生長する。製剤は、細胞単層膜の頂端側または側底側に置き、輸送は、膜の反対側の薬剤濃度の測定を通じて決定される。
PAMPAモデルを使ったSAMe輸送への没食子酸プロピルの効果
PAMPA(parallel artificial membrane permeability assay)モデルを用いて、没食子酸プロピルが存在する場合と存在しない場合のSAMe透過性を測定した。PAMPAモデルは、胃腸管を含むさまざまな障壁への透過と高い相関関係を示すように開発されてきた。ここではそれらが、重要である。これらの膜は、Caco−2細胞の単層膜と異なり密着結合を含まず、したがって、傍細胞への輸送を可能にしていない。
ラニチジンおよびメトホルミンのインビトロの輸送に対する没食子酸プロピルの効果
没食子酸プロピルおよび、ラニチジンまたはメトホルミンのいずれかを使って上記の実施例3で行ったのと同様の実験を行ったが、ラニチジンおよびメトホルミン両方は、公知の傍細胞腸輸送メカニズムを有する(Bourdet and Thakker, Pharm. Res. (2006) June; 23(6):1165-77 and Proctor, W.R. et al., Drug. Metab. Dispos. (2008) Aug; 36(8): 1650-8)。
さまざまな用量の没食子酸プロピルの存在下でビーグルの血漿でSAMe値が増加した
S−アデノシル−L−メチオニン二硫酸塩トシル酸塩の顆粒(400mgのSAMeイオンに相当)と以下の表4に列挙するさまざまな量の没食子酸プロピルを混合させてSAMeおよびさまざまな量の没食子酸プロピルを含む錠剤を生成した。それぞれの混合物を錠剤の形に圧縮、コーティングし、次いで溶解プロファイリングおよびビーグル犬を使ったインビボでの薬物動態学的分析を行った。
・USP Apparatus II、100RPMで操作
・液相:1Lの酵素を含まないUSP人工胃液、pH1.2、37℃
・水性緩衝液相−1Lの酵素を含まないUSP人工腸液、pH6.8またはpH6.0、37℃
・錠剤を酸性の相に2時間曝し、緩衝液相に移した
・酸性の相に2時間曝した後、所定の間隔で緩衝液相中の一定分量を取り出す
・試料をn/10HCLを用いて1→10に希釈する、および
・薬物濃度は、分光光度法により、258mmで測定される。
没食子酸プロピルは、外因性SAMeのヒトの血漿レベルを著しく増加させる
SAMeおよび没食子酸プロピルを含む錠剤を使用して、第1相の臨床研究を行った。健康なヒトのボランティアを使って、SAMeの用量を400mg〜1600mgまで段階的に増大させて行った。これらのSAMe−没食子酸プロピル製剤を、別のSAMe臨床試験において広範囲に研究が行われ、最も一般的に使用、市販されているSAMe製品のうちの1つと比較した。
SAMe組成物の性別効果評価
外因性SAMeの投与により複数の効果があるが、その多くは、一方の性に限られることで知られている。一般的に男性はより身体が大きく、血液量が多い;より高い体格指数(BMI)および2つの性別間でメチル化状態が異なることに加え、特定の遺伝子多型が存在する、などこれらを含む外因性SAMeの薬物動態の性差を説明するさまざまな他の理論がある。
Claims (24)
- 疾病または疾患を処置するための経口投与用医薬の製造において使用するための、外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む組成物であって、没食子酸エステルと外因性S−アデノシルメチオニンの比が5:1〜1:400であり、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む経口組成物であって、約1〜5mg、または約5〜10mg、または約10〜50mg、または約50〜100mgの没食子酸エステルを含み、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- SAMeおよび1つまたはそれ以上の没食子酸エステルを含む経口組成物であって、機能性コーティングを含む単位剤形であり、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- SAMeおよび1つまたはそれ以上の没食子酸エステルおよび1つまたはそれ以上の流動促進剤を含む経口組成物であって、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む生物学的利用能の高い経口組成物であって、選択された対象群に投与された場合、前記選択された対象群において、100mgのSAMeイオン当たり、少なくとも約120ng/mLの平均最高SAMe血漿濃度(平均Cmax)を提供し、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 疾病または疾患を処置するための経口投与用医薬の製造において使用するための、外因性S−アデノシルメチオニンおよび1つまたはそれ以上の没食子酸エステルを含む組成物であって、従来のSAMe製剤と比較して改善された副作用特性を提供し、1つまたはそれ以上の没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 没食子酸エチル、没食子酸プロピル、没食子酸イソアミル、および没食子酸オクチルからなる群から選択される没食子酸エステルを含む、(a)対象においてSAMeの血漿レベルを高めるため、および/または(b)腸の粘膜壁または上皮細胞を通してSAMeの吸収を増加させるための経口組成物であって、さらにSAMeを含むか、またはSAMeと組み合わせて対象に投与される組成物。
- 対象の栄養状態を改善するための、外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む経口組成物であって、少なくとも20重量%のSAMeを含み、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 対象の栄養状態を改善するための、外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む経口組成物であって、前記没食子酸エステルは、没食子酸エチル、没食子酸プロピル、没食子酸イソアミル、および没食子酸オクチルからなる群から選択される、組成物。
- 精神または精神医学的疾患(例えば、それぞれうつ病および物質関連疾患に例示される精神病性/気分障害または非精神病性精神疾患)、神経系疾病/疾患(例えば、アルツハイマー病に例示される中枢神経系疾病)、別の神経学的な疾病/疾患(例えば、頭痛および睡眠障害)、中枢神経系の損傷に関連する状態、肝臓疾病/疾患(例えば、アルコール性肝臓疾病)、がん(例えば、固形および血液媒介のがん)、関節疾病/疾患(例えば、関節炎)、炎症性疾病/疾患(例えば、潰瘍性大腸炎)、自己免疫疾病/疾患(例えば、全身性エリテマトーデスおよびリウマチ性関節炎)、変性疾病/疾患(例えば、筋萎縮性側索硬化症)、軟部組織疾病/疾患(例えば、線維筋痛症疾患)、疼痛性疾病/疾患、過剰または低メチル化に関する遺伝性疾患、胃腸疾病/疾患、レッシュ・ナイハン症候群、および酸化またはフリーラジカル損傷を全体的または部分的な原因とする疾患から成る群から選択されるがそれに限定されない疾病または疾患を対象において治療または防止および/または予防するための経口組成物であって、SAMeおよび1つまたはそれ以上の没食子酸エステルを含み、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 外因性S−アデノシルメチオニンおよび少なくとも1つの没食子酸エステルを含む、外因性SAMeの1日投与量を低減するための経口組成物であって、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- SAMeの血漿レベルを高めるための、1つまたはそれ以上の没食子酸エステルを含む経口組成物であって、さらにSAMeを含むか、またはSAMeと組み合わせて対象に投与され、前記没食子酸エステルは、没食子酸エチル、没食子酸プロピル、没食子酸イソアミル、および没食子酸オクチルからなる群から選択される、組成物。
- SAMeのレベルをインビボで改善するための、1つまたはそれ以上の没食子酸エステルを含む経口組成物であって、さらにSAMeを含むか、またはSAMeと組み合わせて対象に投与され、前記没食子酸エステルは、没食子酸エチル、没食子酸プロピル、没食子酸イソアミル、および没食子酸オクチルからなる群から選択され;改善されたSAMeレベルは、投与されたSAMeイオン100mg当たり少なくとも約120ng/mLの平均最高SAMe血漿濃度(平均Cmax)により測定され、および/または改善されたインビボSAMeレベルは、前記1つまたはそれ以上の没食子酸エステルを含まない従来のSAMe投与形態と比較して測定される、組成物。
- 対象に投与された外因性SAMeの薬物動態パラメータを改善するための、少なくとも1つの没食子酸エステルを含む経口組成物であって、少なくとも1つの生理学的に有効な量のSAMeを含む非経口ではない組成物と組み合わせて対象に投与され、前記薬物動態パラメータは、対象において、同じまたは同様であるが没食子酸エステルを含まないSAMe製剤が投与された対照群との比較においてCmax、AUC、およびそれらの組み合わせのうちの1つによって測定可能であり、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 外因性SAMeおよび少なくとも1つの没食子酸エステルを含む、外因性SAMeのインビボ副作用特性を軽減または改善するための経口組成物であって、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、組成物。
- 約10〜1200mgのSAMeを含む請求項1〜15のいずれかに記載の組成物。
- 没食子酸エステルと外因性S−アデノシルメチオニンの比(重量:重量)が、1:1〜1:100または1:2〜1:80である請求項1〜16のいずれかに記載の組成物。
- 0.1〜80重量%、0.25〜50重量%、0.25〜25重量%、0.25〜10重量%、または0.5〜10重量%の没食子酸エステルを含む請求項1〜17のいずれかに記載の組成物。
- 外因性SAMeイオンの用量が少なくとも10mgである請求項1〜18のいずれかに記載の組成物。
- 非カプセル剤形である請求項1〜19のいずれかに記載の組成物。
- 対象に有効量で投与される、対象の疾病または疾患を処置するための請求項2〜5および7〜15のいずれかに記載の組成物。
- 疾病または疾患の処置が、精神または精神医学的疾患、神経系疾病または疾患、神経学的疾病または疾患、中枢神経系の損傷に関連する状態、肝臓疾病または疾患、がん、関節疾病または疾患、炎症性疾病または疾患、自己免疫疾病または疾患、変性疾病または疾患、軟部組織疾病または疾患、疼痛性疾病または疾患、過剰または低メチル化に関連する遺伝性疾患、胃腸疾病または疾患、循環器疾病または疾患、アテローム性動脈硬化症、レッシュ・ナイハン症候群、および酸化またはフリーラジカル損傷を全体的または部分的な原因とする疾患から成る群から選択される疾病または疾患の処置、またはその処置効果の発現速度の増加である請求項1、6および21のいずれかに記載の組成物。
- 精神または精神医学的疾患が、不安障害、統合失調症、大うつ病性障害、大うつ病、臨床的うつ病、気分変調性障害、不安うつ病、非定型うつ病、メランコリー型うつ病、緊張病性うつ病、状況性うつ病(situational depression)、反応性うつ病、高齢期うつ病、季節性情動障害(SAD)、小うつ病、産後うつ病、炎症性うつ病、高齢期うつ病、短期再発性うつ病(brief recurrent depression)、軽症うつ病、治療抵抗性うつ病(TRD)、併存うつ病、パーキンソン病うつ病、HIV関連うつ病、多発梗塞性認知症、および双極性疾患から成る群から選択され;
炎症性疾病または疾患が、全身性ループス、炎症性腸疾患、アレルギー性鼻炎、接触性皮膚炎、喘息、自己免疫性肝炎、および骨盤内炎症性疾患から成る群から選択され;
うつ病性疾患が、がん、パーキンソン病、およびHIVから成る群から選択される1以上の疾病または疾患の治療を受けるかまたは受けている対象に生じる併存うつ病であり;
肝臓疾病または疾患が、アルコール性肝臓疾患、非アルコール性脂肪肝疾患、ウイルス性または非ウイルス性肝炎、肝臓がん、酸化肝臓疾患、薬剤性の肝臓損傷、胆汁鬱滞、および肝硬変から成る群から選択され;
がんが、肝臓がん、結腸がん、直腸がん、胃がん、食道がん、および腺がんから成る群から選択され;
関節疾病または疾患が、関節炎または変形性関節症である、
請求項22に記載の組成物。 - SAMeの取り込みを改善するための経口投与用製剤の製造方法であって、外因性SAMeおよび少なくとも1つの没食子酸エステルを組み合わせ、前記外因性SAMeおよび少なくとも1つの没食子酸エステルを、追加の賦形剤を用いるかまたは用いずにカプセルまたは非カプセルに製剤化することを含み、没食子酸エステルは、没食子酸エチル、没食子酸イソアミル、没食子酸プロピル、および没食子酸オクチルから成る群から選択される、製造方法。
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