JP6077053B2 - 体重減少の達成および肥満症の治療のための漸増用量投与計画(escalatingdosingregimen) - Google Patents
体重減少の達成および肥満症の治療のための漸増用量投与計画(escalatingdosingregimen) Download PDFInfo
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- JP6077053B2 JP6077053B2 JP2015102962A JP2015102962A JP6077053B2 JP 6077053 B2 JP6077053 B2 JP 6077053B2 JP 2015102962 A JP2015102962 A JP 2015102962A JP 2015102962 A JP2015102962 A JP 2015102962A JP 6077053 B2 JP6077053 B2 JP 6077053B2
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Description
本願は、2008年6月9日に出願された米国特許出願第12/135,953号の一部継続出願であって、その開示は参照することによって援用される。
小児および成人の両方における肥満症の有病率は、先進国、特に米国のみならず、中国およびインドなどの多くの発展途上国においても上昇している。膝および足首関節悪化などの身体的問題から、自尊心に関わる問題および体重が重い人々に対する社会の態度に起因する情緒的問題に至るまで、人々の生活の多くの側面が肥満症によって影響されている。肥満症に起因する医学的問題は重篤なものとなり得、しばしば生命を脅かし、糖尿病、息切れならびに喘息および肺高血圧症などの他の呼吸器疾患、胆嚢疾患、脂質異常症(例えば、高コレステロールまたは高濃度のトリグリセリド)および脂質異常症の高血圧症、骨関節炎および他の整形外科的障害、逆流性食道炎(胸やけ)、いびき、睡眠時無呼吸、月経不順、不妊症、妊娠と関連する障害、痛風、冠動脈疾患および他の心臓疾患などの心血管障害、筋ジストロフィー、ならびに低αリポタンパク血症、家族性複合型高脂血症、およびインスリン抵抗性シンドロームXを含むシンドロームXなどの代謝障害を含む。さらに、肥満症は特定の癌、特に結腸癌、直腸癌、前立腺癌、乳癌、子宮癌、および子宮頸癌の発生率上昇と関連する。
本発明は、体重減少を達成し、肥満症を治療し、かつ、過剰体重もしくは肥満症に起因し、またはこれらと関連する状態を治療するための新規なトピラメート組成物および方法を提供する。該組成物は単一活性薬剤としてトピラメートを含有してよいが、より典型的には、少なくとも1つの交感神経刺激薬と組み合わせてトピラメートを含有する。用語「交感神経刺激薬(sympathomimetic agent)」は専門用語であり、交感神経系の刺激を模倣または変化する薬剤または化合物を指す。代表的な交感神経刺激薬は、フェンテルミンおよびブプロピオンを含む。好ましくは、該トピラメートおよび該交感神経刺激薬は単一剤形に含有され、該交感神経刺激薬の即時放出、ならびに該トピラメートの制御放出、例えば、持続放出、遅延放出、または持続放出および遅延放出の両方を提供する。
定義および命名法:
本明細書および添付の特許請求の範囲にて用いられている単数形「a」、「an」および「the」は、文脈においてはっきりと別段の指示がない限り、複数の指示対象を含むことに留意しなければならない。それゆえ、例えば、「活性薬剤(an active agent)」は単一の活性薬剤のみならず、2つ以上の異なる活性薬剤の組み合わせも指し、「剤形(a dosage form)」は単一剤形のみならず剤形の組み合わせをも指す、などである。
本発明は、体重減少を達成し、かつ、肥満症、過剰体重または肥満症と関連する状態、糖尿病(肥満症と関連しているかどうかに関わらず)、ならびに以下で説明するような他の状態および障害を治療するための新規な方法および組成物を提供する。米国疾病対策センターによると、過体重(該用語は本明細書で用語「過剰体重」と同義的に用いられている)であることの臨床的定義は、25.0〜29.9kg/mの間のボディー・マス・インデックス(BMI)を有していることである;BMIは、個人の体重(キログラム)と身長(メートル)を掛け合わせることによって計算される。CDCは肥満症を30以上のBMIを有するもの定義している。1つの実施態様では、本発明は体重減少を達成し、かつ、過体重、肥満症、ならびに過剰体重および肥満症と関連する状態を治療する方法を提供し、交感神経刺激薬フェンテルミンおよび抗痙攣剤トピラメートの組み合わせの投与を含む。
本明細書で用いられている用語「トピラメート」は、2,3,4,5−ビス−(O)−(1−メチルエチリデン)−β−D−フルクトピラノーススルファメートのみならず、個々のエナンチオマー、個々のジアステレオマー、またはその混合物を包含する。本明細書で用いられている用語「トピラメート」は、トピラメート塩のみならず、多形、溶媒和物(水和物および混合溶媒和物、ならびに塩の水和物を含む)、共結晶(例えば、他の化合物または他の形態のトピラメートとの共結晶)、非晶質、ならびに式(I)の化合物の無水物形態をも包含する。該化合物がスルファミン酸誘導体であるという事実から分かるように、本発明と関連して有用なトピラメート塩は、医薬的に許容される塩基付加塩である。該塩は、式(I)の化合物のスルファミン酸基と結合する医薬的に許容されるカチオンを提供する塩基から製造される。適切な医薬的に許容されるカチオンは有機および無機カチオンの両方を含み、ナトリウム、ナトリウム、カリウム、リチウム、マグネシウム、カルシウム、アルミニウム、亜鉛、プロカイン、ベンザチン、クロロプロカイン、コリン、ジエチルアミン、エチレンジアミン、N−メチルグルカミン、ベネタミン、クレミゾール、ジエチルアミン、ピペラジン、トロメタミン、トリエチルアミン、エタノールアミン、トリエタノールアミン、アルギニン、リジン、ヒスチジン、トリブチルアミン、2−アミノ−2−ペンチルプロパノール、2−アミノ−2−メチル−1,3−プロパンジオール、トリス(ヒドロキシメチル)アミノメタン、ベンジルアミン、2−(ジメチルアミノ)エタノール、バリウムまたはビスマス対イオン(barium or bismuth counter ions)を含み、これらに限定されない。特に好ましいカチオンはナトリウム、リチウム、およびカリウムである。上記で参照した他の形態のトピラメートは、当該技術分野で周知の方法を用いて製造されてよい;例えば、米国特許第7,351,695号を参照のこと。本発明の方法は、トピラメートの単独または、より好ましくは、交感神経刺激薬と組み合わせた投与のための投与計画を含む。特定の態様では、本発明は、例えば、ブプロピオンまたはフェンテルミンと組み合わせたトピラメートを含む医薬組成物の投与のための投与計画を提供する。
本発明の有用性を見出しうる特に興味深い状態は、過体重、肥満症ならびに過剰体重および肥満症としばしば関連し、および/またはそれらに起因する状態を含む。本明細書で提供する投与計画に従って投与されるトピラメート組成物および組み合わせは、有意な治療効果および有害作用の減少を生じるため、これらの医薬組成物を非常に有効な治療法としており、特に過体重、肥満症ならびに/または、過剰体重もしくは肥満症自体と関連し、および/もしくはこれらに起因する状態を含む関連状態の治療に有効なものとしている。それゆえ、本発明の併用療法の治療計画での治療に適切な対象は、肥満症と関連する状態を患う個人を含み、該状態は下記を含み、これらに限定されない:
糖尿病、インスリン抵抗性、および耐糖能異常;
肺高血圧症、喘息、および息切れなどの呼吸器疾患;
胆嚢疾患;
脂質異常症、例えば、高コレステロール、および高濃度のトリグリセリドなど;
骨関節炎および他の整形外科的障害;
逆流性食道炎;
睡眠時無呼吸および大いびきを含む、睡眠と関連する有害状態;
月経不順、不妊症、および妊娠合併症;
痛風;
高血圧、すなわち、高血圧症;
冠動脈疾患および他の心臓疾患などの心血管障害;
筋ジストロフィー;
脳卒中、特に血栓脳卒中および深部静脈血栓症(DVT);
片頭痛;
低αリポタンパク血症、家族性複合型高脂血症、およびインスリン抵抗性シンドロームXを含むシンドロームXなどの代謝障害;ならびに
結腸癌、直腸癌、腎臓癌、食道癌、胆嚢癌、膵臓癌、前立腺癌、乳癌、子宮癌、卵巣癌、子宮内膜癌、および子宮頸癌。
本発明の方法を実施するためのパッケージ化された医薬製剤も提供される。パッケージ化された製剤は密封容器内にある本発明の組成物を含有し、典型的には、各々ブリスター・パックなどの密封ハウジング(sealed housing)内にある個々の剤形を複数含有するが、単一密封容器内にある1つ以上の剤形も含有しうる。任意に、用量漸増(dose titration)および用量増加(dose escalation)のために、一方または両方の活性薬剤の低用量を有する剤形も含まれてよい。
押出球形化プロセスを用いて制御放出トピラメートビーズを製造し、トピラメート、40.0%w/w;微結晶セルロース(アビセルPH102(Avicel(登録商標)PH102))、56.5%w/w;およびメトセルA15LV(Methocel(商標)A15LV)、3.5%w/wから成るマトリックスコアを製造する。次いで、該トピラメートコアをエチルセルロース、5.47%w/w、およびポビドンK30、2.39%w/wでコーティングした。
成分 %w/w
トピラメート 36.85
微結晶セルロース、
(Avicel(登録商標)PH102) 52.05
メチルセルロース
(Methocel(商標)A15LV) 3.22
エチルセルロース 5.47
ポリビニルピロリドン
(ポビドンK30) 2.39
フェンテルミンと組み合わせた本発明のトピラメートの制御放出製剤と、即時放出トピラメート(トパマックス(Topamax(登録商標)))とを比較した研究において、本発明のトピラメートの制御放出製剤はフェンテルミン曝露に対して10〜15%低い効果を有した(図2)。
Claims (11)
- 制御放出トピラメート製剤の有効量、および
即時放出フェンテルミン製剤の有効量
を含むカプセルハウジングを含む、対象において肥満症、糖尿病または関連状態を治療するための組成物であって、
即時放出フェンテルミン製剤がフェンテルミン塩酸塩でコーティングされた不活性コアのビーズを含み、
制御放出トピラメート製剤がマトリックスコア内にトピラメートの制御放出ビーズ、結合剤、およびポリマー充填剤を含み、マトリックスコアがエチルセルロースおよびポリビニルピロリドンを含む遅延放出コーティングを有する組成物。 - ポリマー充填剤が微結晶セルロースを含む、請求項1に記載の組成物。
- 結合剤がメチルセルロースを含む、請求項1または2に記載の組成物。
- 制御放出トピラメート製剤の有効量、および
即時放出フェンテルミン製剤の有効量
を含む錠剤を含む、対象において肥満症、糖尿病または関連状態を治療するための組成物であって、
制御放出トピラメート製剤がトピラメート、結合剤、およびポリマー充填剤を含み、
錠剤が少なくとも2つの分離した区分を含有し、その少なくとも1つが即時放出フェンテルミン製剤を含有し、その少なくとももう一方が制御放出トピラメート製剤を含有する組成物。 - ポリマー充填剤が微結晶セルロースを含む、請求項4に記載の組成物。
- 結合剤がメチルセルロースを含む、請求項4または5に記載の組成物。
- トピラメートの有効量が23mgであり、フェンテルミンの有効量が3.75mgである、請求項1〜6のいずれか1項に記載の組成物。
- 4.92mgのフェンテルミン塩酸塩が3.75mgのフェンテルミンを提供する、請求項7に記載の組成物。
- トピラメートの有効量が46mgであり、フェンテルミンの有効量が7.5mgである、請求項1〜6のいずれか1項に記載の組成物。
- 9.84mgのフェンテルミン塩酸塩が7.5mgのフェンテルミンを提供する、請求項9に記載の組成物。
- トピラメートの有効量が92mgであり、フェンテルミンの有効量が15mgである、請求項1〜6のいずれか1項に記載の組成物。
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