JP5231242B2 - ヌクレオチド及びヌクレオシド系逆転写酵素阻害剤(テノホビル及びラミブジン)を剤形の異なる部分に含む医薬組合せ - Google Patents
ヌクレオチド及びヌクレオシド系逆転写酵素阻害剤(テノホビル及びラミブジン)を剤形の異なる部分に含む医薬組合せ Download PDFInfo
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Classifications
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- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61P31/18—Antivirals for RNA viruses for HIV
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Description
レトロウイルス複製の共通した特徴は、ウイルスにコードされたプロテアーゼにより、ポリタンパク質前駆体が多くの翻訳後処理を受け、ウイルス構築及び機能にとって必要である成熟ウイルスタンパク質を生成することである。この処理の阻害は、通常、感染ウイルスの生成を抑制する。論文により、HIVコード化プロテアーゼの遺伝的不活性化が、未成熟な非感染ウイルス粒子の生成をもたらすことが報告されている。これらの結果は、HIVプロテアーゼの阻害が、AIDSの治療、及びHIVによる感染症の予防又は治療の実行可能な方法であることを示している。
今日、この目的に利用可能な様々な組合せが構成されており、組合せ投与計画を考案する幾つかの試みが行われている。一例には、GlaxoSmithKlineの登録商標Combivirとして商業的に入手可能な、合成ヌクレオシド類似体ラミブジン(150mg)とジドブジン(300mg)との組合せがある。別の当該組合せには、Glaxoの特許出願第WO 03/101467号に記載されている、ヌクレオシド類似体アバカビルとラミブジンとの組合せがある。
ラミブジンと他のヌクレオシド系逆転写酵素阻害剤、特にジドブジンAZTとの組合せは、WO 92/20344、WO 98/18477、及びWO99/55372に記載されている。
エファビレンツは、HIVの治療のために、SUSTIVA(登録商標)の名称でBristol-Myers Squibb Coから商業的に入手可能であり、例えば、米国特許第5,519,021号、第5,663,1699号、第5,811,423号、及び第6,238,695号に記載されている。
組合せ療法は、患者に摂取する一日の投与量を少なくし、かつ投与スケジュールを単純化する。従って、患者コンプライアンスを向上する。また、組合せ療法は、薬剤効果を増大する。組合せ療法の使用は、毒性を減らすと共に同等の抗ウイルス作用を得ることができる。
(a)ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体、及び
(b)ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体を含み、
該ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体が、該剤形において、該ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体と異なる領域内に提供されている、前記医薬製剤を提供する。
第三の態様において、
i)ラミブジン、
ii)ヌクレオチド系逆転写酵素阻害剤、及び
iii)非ヌクレオシド系逆転写酵素阻害剤
を含む医薬品を提供する。
本発明は、さらに、ウイルス感染症の治療又は予防における、同時、別個、又は逐次的使用のための医薬組成物を提供する。特に、本発明は、同時、別個、又は逐次的使用のための、本発明の医薬製剤及び非ヌクレオシド系逆転写酵素阻害剤を含む医薬品を提供する。
従って、本発明は、耐性の発現のなく長期間、患者のHIVレベルを検出不可能なくらいに低下させ、かつCD4細胞数を上昇させる、AIDSの有効かつ長期持続療法を提供する。
本発明の第一の態様において、ヌクレオシド系逆転写酵素阻害剤は、好ましくは、ラミブジン、アバカビル、エムトリシタビン、ジドブジン、スタブジン、又はそれらの生理的機能性誘導体から選択される。好ましくは、ラミブジンを使用する。ヌクレオチド系逆転写酵素阻害剤は、好ましくは、テノホビルDF、又はアデホビルから選択され、好ましくはテノホビルDFである。
第三の態様において、ヌクレオチド系逆転写酵素阻害剤は、好ましくは、テノホビルDF、又はアデホビル、或いはそれらの生理的機能性誘導体から選択される。好ましくはテノホビルDFを使用する。非ヌクレオシド系逆転写酵素阻害剤は、好ましくは、エファビレンツ、ネビラピン、デラビルジン、又はそれらの生理的機能性誘導体から選択される。好ましくは、非ヌクレオシド系逆転写酵素阻害剤は、エファビレンツである。
本発明の組成物又は医薬品は、ウイルス感染症、特にヒト免疫不全ウイルス(HIV)及びAIDSをもたらす関連障害を含み得るレトロウイルス感染症の治療に有用であり得る。
本明細書で使用するように、用語「生理的機能性誘導体」は、本発明に従って投与される場合、指定された活性と同等又はほぼ同等の生理的機能を有する、医薬として活性な化合物を意味する。本明細書で使用するように、用語「生理的機能性誘導体」は、ヌクレオシド-、ヌクレオチド-、又は非ヌクレオシド系逆転写酵素阻害剤の任意の、医薬として許容し得る塩、溶媒和物、エステル、プロドラッグ、誘導体、鏡像異性体、又は多形体を含む。
本明細書で使用するように、単語「治療」の言及は、確立された疾病、感染、又はその症状の予防及び治療の双方にまで及ぶ。
単一薬剤の治療計画は、通常、長期的な治療を必要とし、好ましくない副作用の徴候を増加させる。さらに、単一薬剤の療法は、HIV種の変異に対して特に無防備であり、HIVの薬剤耐性変異体が生じる。
従って、本発明の組合せ療法は、AIDS治療の有効性を向上させ、個々の治療剤に対する耐性の発現を抑制する方法を提供する。
ラミブジン(3TCとしても知られている)は、合成ヌクレオシド類似体であり、化学的には(2R,cis)-4-アミノ-1-(2-ヒドロキシメチル-1,3-オキサチオラン-5-イル)-(1H)-ピリミジン-2-オン(Epivir(登録商標))として知られている。ラミブジンは、HIV、及びHBVなどの他のウイルスに対して抗ウイルス活性を示す。
また、個別又は逐次的投与のための単位剤形において、本発明に使用されるNRTIs及びNtRTIsのいずれか2つを、NNRTIを含む剤形と組み合わせることが可能である。好ましくは実施態様において、典型的な単位剤形は、ラミブジン及びテノホビルDF又はそれらの生理的機能性誘導体を含むことができ、さらに単位剤形は、エファビレンツ又はその生理的機能性誘導体を含むことができる。この点において、本発明は、(i)1種以上の医薬として許容し得る担体又は賦形剤とともにラミブジン及びテノホビルDF又はそれらの生理的機能性誘導体を含む、任意に二層状錠剤の形態である第一医薬製剤;及び(ii)1種以上の医薬として許容し得る担体又は賦形剤とともにエファビレンツ又はその生理的機能性誘導体を含む第二医薬製剤を含有した、ウイルス感染症、特にレトロウイルス感染症、とりわけ感染動物のHIV感染又は作用の治療又は予防において個別又は逐次的使用のための、医薬品を提供する。
本発明の医薬品は、都合よく、各化合物について固有の投与量範囲を含む経口剤形において、3種の活性化合物を含む個別又は逐次的投与で、医薬配合剤の投与が可能である。好ましくは、NRTI及びNtRTIを含む単位剤形を提供する。好ましくは、個別又は逐次的投与のために、NNRTIを含む追加の剤形を提供する。
好ましくは、テノホビルDFは、1単位剤形あたり75〜600mg、好ましくは300mgの範囲で提供され得る。
好ましくは、エファビレンツは、1単位剤形あたり50〜600mg、好ましくは600mgの範囲で提供され得る。
有する場合、錠剤サイズを大きくするために、希釈剤又は膨張性薬剤を選択することができる。当業者は、医薬としての有利性に必須な硬度、破砕性、及び崩壊時間を提供する膨張性薬剤を選択するため、公知の方法を利用することができる。適切な希釈剤には、微結晶性セルロース、及びラクトースなどがある。希釈剤は、好ましくは、製剤の5重量%〜50重量%の量で存在する。
本発明での使用に適した崩壊剤は、1種以上のセルロース、及びそれらの誘導体、アルギン酸塩、寒天、特定の複合ケイ酸塩(complex silicilates)、デンプン、改質デンプン及びそれらの誘導体、ポリビニルピロリドンなどを含むことができる。好ましい崩壊剤には、デンプングリコール酸ナトリウム、及び/又はクロスカルメロースナトリウムがある。好ましくは、崩壊剤は、剤形の0.5重量%〜30重量%の量で存在する。
好ましい実施態様において、製剤は、二層状錠剤の形態である。別の好ましい実施態様において、医薬品は、二層状錠剤及び形成された単位錠剤製剤の形態である。
さらに好ましくは、本発明の製剤又は医薬品において、ラミブジン又はその生理的機能性誘導体を含む錠剤の第一層は、5〜55重量%のラミブジン、約10〜50重量%の微結晶性セルロース、約2〜30重量%のデンプングリコール酸ナトリウム、約1〜10重量%のデンプン、及び約0.25〜2.5重量%のステアリン酸マグネシウムを含む。
さらに好ましくは、該錠剤の第二層は、約35〜85重量%のテノホビルDF、約5〜50重量%のラクトース又は微結晶性セルロース、約1〜10重量%のデンプン、約1〜20重量%のデンプングリコール酸ナトリウム、及び約0.2〜2重量%のステアリン酸マグネシウムを含む。
次に、適切な圧縮装置を用いて、両層の潤滑化顆粒を共に圧縮する。
両層は、任意に着色剤を含むことができる。
本発明の錠剤の各部分は、湿式造粒法、又は直接的圧縮、又は乾式造粒法により製造することができる。比較的高投与量のラミブジンを考慮して、湿式造粒法を使用することが好ましい。
これから、特定の実施態様のみであり、本発明の範囲を限定しない下記実施例に準拠して、本発明をさらに記載する。
層Iの調製は、希釈剤、崩壊剤、及び任意に適切な着色剤をラミブジンとともに混合する段階、次にその混合物を潤滑する段階を含む。層IIの調製は、希釈剤をテノホビルDFとともに混合する段階;顆粒を得るために、さらに水及び適切な結合剤を用いて、それを顆粒化する段階;得られた顆粒を乾燥し、かつ該顆粒を分粒する段階;前記顆粒を適切な着色剤及び崩壊剤とともに再度混合する段階;及び該顆粒を潤滑する段階を含む。適切な圧縮装置を用いて、両層の潤滑化顆粒を共に圧縮する。
テノホビル及びラクトースを予め混合したものを調製する。これを、クロスカルメロースナトリウム及びデンプンと乾燥混合する。精製水中のデンプン及びポリソルベート80の結合剤溶液を調製する。その結合剤溶液を用いて、乾燥混合物を顆粒化し、湿顆粒を乾燥し、分粒し、潤滑する。
ラミブジン、微結晶性セルロース、デンプングリコール酸ナトリウム、及び着色剤の乾燥混合物を調製する。これを、結合剤溶液(デンプンペースト)を用いて顆粒化する。その顆粒を分粒し、乾燥し、潤滑する。
その錠剤を圧縮し、着色レディミックス溶液(colour redimix solution)を用いてコーティングする。
本発明が改質できることは明らかであろう。
Claims (15)
- 単一単位剤形の医薬製剤であって、該剤形が、
(a)ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体、及び
(b)ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体を含み、
該製剤が多層状錠剤、又はコーティングコア錠剤の形態であり、
該ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体が、該剤形において、ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体と異なる領域内に提供されている、前記医薬製剤。 - 前記ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体が、前記剤形の第一領域内に提供され、かつ前記ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体が、前記剤形の第二領域内に提供され、該第一領域はヌクレオチド系逆転写酵素阻害剤を含まない又は実質的に含まず、かつ該第二領域はヌクレオシド系逆転写酵素阻害剤を含まない又は実質的に含まない、請求項1記載の医薬製剤。
- 多層状錠剤の形態であり、前記錠剤の第一層が前記ヌクレオシド系逆転写酵素阻害剤又はその生理的機能性誘導体を含み、かつ前記錠剤の第二層が前記ヌクレオチド系逆転写酵素阻害剤又はその生理的機能性誘導体を含み、前記第一層及び/又は第二層が少なくとも1種の医薬として許容し得る賦形剤をさらに含む、請求項1又は2記載の医薬製剤。
- 前記多層状錠剤が、二層状錠剤又は三層状錠剤である、請求項3記載の医薬製剤。
- 前記多層状錠剤が三層状錠剤であり、かつ前記錠剤の第三層が、前記第一層と第二層との中間にあり、かつ任意に前記ヌクレオシド系逆転写酵素阻害剤及び前記ヌクレオチド系逆転写酵素阻害剤を含まない又は実質的に含まない、請求項4記載の医薬製剤。
- 前記コーティング錠剤が、前記第一領域又は第二領域のうちの一方を含むコア、及び前記第一領域又は第二領域のうちの他方を含むコーティング層から形成されている、請求項1又は2記載の医薬製剤。
- 前記コーティング錠剤が、前記コアとコーティング層との間に中間層を含み、かつ前記錠剤の中間層が任意に前記ヌクレオシド系逆転写酵素阻害剤及び前記ヌクレオチド系逆転写酵素阻害剤を含まない又は実質的に含まない、請求項6記載の医薬製剤。
- 前記ヌクレオシド系逆転写酵素阻害剤が、ラミブジン、アバカビル、エミトリシタビン、ジドブジン、又はスタブジン、或いはそれらの生理的機能性誘導体である、請求項1〜7のいずれか1項記載の医薬製剤。
- 前記ヌクレオチド系逆転写酵素阻害剤が、テノホビルDF又はアデホビル、或いはそれらの生理的機能性誘導体である、請求項1〜8のいずれか1項記載の医薬製剤。
- 前記ヌクレオシド系逆転写酵素阻害剤がラミブジン又はその生理的機能性誘導体であり、かつ前記ヌクレオチド系逆転写酵素阻害剤がテノホビルDF又はその生理的機能性誘導体である、請求項1〜9のいずれか1項記載の医薬製剤。
- 単位剤形あたり、前記ヌクレオシド系逆転写酵素阻害剤を50mg〜600mg含み、かつさらに、単位剤形あたり、前記ヌクレオチド系逆転写酵素阻害剤を75mg〜600mg含む、請求項1〜10のいずれか1項記載の医薬製剤。
- 請求項1〜11のいずれか1項記載の医薬製剤を含み、さらに非ヌクレオシド系逆転写酵素阻害剤を含む、医薬品。
- 前記非ヌクレオシド系逆転写酵素阻害剤が、エファビレンツ、ネビラピン、又はデラビルジン、或いはそれらの生理的機能性誘導体である、請求項12記載の医薬品。
- 前記非ヌクレオシド系逆転写酵素阻害剤が第一剤形として配合され、かつ前記ヌクレオシド系逆転写酵素阻害剤及び前記ヌクレオチド系逆転写酵素阻害剤が第二の別個の単位剤形として配合されている、請求項12又は13のいずれか1項記載の医薬品。
- 前記ヌクレオシド系逆転写酵素阻害剤がラミブジンであり、前記ヌクレオチド系逆転写酵素阻害剤がテノホビルDFであり、かつ前記非ヌクレオシド系逆転写酵素阻害剤がエファビレンツである、請求項12記載の医薬品。
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DE602006015721D1 (de) | 2010-09-02 |
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KR20080091767A (ko) | 2008-10-14 |
CA2633603C (en) | 2016-09-13 |
AP2008004533A0 (en) | 2008-08-31 |
SI2051703T1 (sl) | 2011-01-31 |
MA30161B1 (fr) | 2009-01-02 |
US20080317852A1 (en) | 2008-12-25 |
BRPI0620705A2 (pt) | 2011-11-22 |
WO2007068934A3 (en) | 2008-02-21 |
EP2051703A2 (en) | 2009-04-29 |
WO2007068934A2 (en) | 2007-06-21 |
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NZ569349A (en) | 2012-01-12 |
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