JP2010525078A - ビタミンd化合物およびワックス状担体を含有する制御放出性経口組成物 - Google Patents
ビタミンd化合物およびワックス状担体を含有する制御放出性経口組成物 Download PDFInfo
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- JP2010525078A JP2010525078A JP2010506520A JP2010506520A JP2010525078A JP 2010525078 A JP2010525078 A JP 2010525078A JP 2010506520 A JP2010506520 A JP 2010506520A JP 2010506520 A JP2010506520 A JP 2010506520A JP 2010525078 A JP2010525078 A JP 2010525078A
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Abstract
Description
米国特許法第119条第(e)項により2007年4月25日出願の米国特許仮出願第60/913853号の利益をこれによって請求する。
調節放出性製剤
下表3に従って、確認された成分を示した量で均一に混合すること、およびその混合物を硬質ゼラチンカプセル中に充填することによって、9種の経口ビタミンD製剤を調製した。製剤9は、従来技術による即放性製剤であり、ここで、MIGLYOL812Nは、トリ(カプリル酸/カプリン酸)グリセリドの商品名であり、米国ニュージャージー州CranfordのCONDEA Chemie GmbHから入手できる。製剤を、ユカタンミニブタ(約10kg)の群に250μgの25−ヒドロキシビタミンD3に相当する単回投与で投与した。各群は5頭の動物を含んでいた。5頭のユカタンミニブタからなる第10群には、250μgに相当する25−ヒドロキシビタミンD3を静脈内注射で投与した。
ミニブタでの経口カプセルの薬物動態研究
本研究の目的は、a)25−ヒドロキシビタミンD3の250μg調節放出性(MR)カプセル×1錠、b)250μgMRカプセル×2錠、c)250μgMRカプセル×4錠、d)1000μgMRカプセル×1錠、e)25−ヒドロキシビタミンD3の250μg即放性(IR)カプセル×1錠、およびf)3日連続で250μgMRカプセル×1錠を投与した後の、雄性ユカタンブタ(体重約45kg)における25−ヒドロキシビタミンD3の全身性吸収を評価することとした。
ミニブタでの経口カプセルによる全身曝露研究
本研究の目的は、十分なビタミンD摂取量を含む食餌で飼育された健常雄性ユカタンブタ(約50〜60kgの体重)における、1日当たり、次のもの、a)25−ヒドロキシビタミンD3の25μg即放性(IR)カプセル(群1)、b)25−ヒドロキシビタミンD3の25μg調節放出性(MR)カプセル(群2)、およびc)25−ヒドロキシビタミンD3の125μgMRカプセル(群3)を21日間投与した後の、25−ヒドロキシビタミンD3全身濃度の増加を評価することとした。
ビーグル犬での経口カプセルの薬物動態研究
25−ヒドロキシビタミンD3の調節放出性カプセルを、ビーグル犬(10kg)に13週間連続して毎日投与した。該MR製剤は、上記実施例1の群7の製剤をベースにして調製した。25−ヒドロキシビタミンD3濃度の相違は、エタノールを相対的に変化させて調整した。
溶出による放出
図27は、上記実施例2による250μgカプセルに関する溶出放出プロフィールを示し、該プロフィールは、24時間の時点で25−ヒドロキシビタミンD3の約72%の平均放出を示した。上記のように、好ましくは、調節放出性製剤は、最初の24時間で薬物の約80%を放出する。
ビタミンD不足の健康成人男性志願者での効力研究
血清中25−ヒドロキシビタミンDを最適濃度(>30ng/mL)まで戻す上での3種の異なるビタミンD製剤の有効性を、ビタミンD不足と診断された健康な非肥満男性での23日間の研究で調べた。製剤の1つ(製剤#1)は、30μgの25−ヒドロキシビタミンD3を含有する、上記実施例1の群7に記載のように調製された軟質ゼラチンカプセルである。第2の製剤(製剤#2)は、中鎖トリグリセリドのオイルに溶解された50,000IUのエルゴカルシフェロールを含有する同一外観の即放性軟質ゼラチンカプセルである。第3の製剤(製剤#3)は、中鎖トリグリセリドのオイルに溶解された50,000IUのコレカルシフェロールを含有するやはり同一外観の即放性軟質ゼラチンカプセルである。この研究には、全部で100名の健康な白色人種およびアフリカ系アメリカ人男性が参加し、そのすべては、30〜45歳であり、15〜29ng/mL(両端を含む)の血清中25−ヒドロキシビタミンD濃度を有する。すべての対象は、研究開始前の60日間および続いて研究終了までの他のビタミンDサプリメントの摂取、および特に問題となるほどの日光曝露を絶つ。研究の1日および2日目に、血清中25−ヒドロキシビタミンDの治療前ベースライン値を確立するため、すべての対象から早朝空腹時血液検体を集める。3日目の朝に、対象からさらなる空腹時血液検体(t=0)を集め、対象を、4つの治療群の1つにランダムに割り振り、朝食前に1つの試験カプセルを投与する。すなわち、群#1の対象には、製剤#1の1カプセルをそれぞれ服用させ、群#2および群#3の対象には、それぞれ、製剤#2または製剤#3の1カプセルをそれぞれ服用させる。群#4の対象には、そっくりのプラセボカプセルを服用させる。群#1の対象には、4日目から22日目までの朝に製剤#1のさらなるカプセルを朝食前にそれぞれ服用させるが、群#2、#3および#4の対象には、さらなるカプセルを服用させない。4、5、6、10、17および23日目(または、投与開始後1、2、3、7、14および20日目)に、治療群に無関係に各対象から早朝空腹時血液検体を採血する。すべての採取した血液を、25−ヒドロキシビタミンDの含有濃度について分析し、データを、ベースライン値の補正を行った後に治療群によって解析する。対象は、4つのすべての治療群において、1〜3日目に採血された空腹時血液検体の分析をベースにしてほぼ16〜18ng/mLの平均ベースライン血清中25−ヒドロキシビタミンD濃度を示す。群#4の対象(対照群)は、研究過程にわたって平均血清中25−ヒドロキシビタミンDの有意な変化を示さない。群#1の対象は、23日目までに少なくとも30ng/mLに到達する着実に増加する平均血清中25−ヒドロキシビタミンDを示す。極めて対照的に、群#2の対象は、投与後の最初の数日間、29ng/mLの最大値に到達する平均血清中25−ヒドロキシビタミンDの著しい増加を示し、その後急速に降下する。研究終了まで、群#2の血清中25−ヒドロキシビタミンDは、ベースラインに比べて有意に低い。群#3の対象は、投与後の最初の2週間を通して平均血清中25−ヒドロキシビタミンDの持続的増加を示し、その後、緩慢ではあるが漸進的な減少が起こる。研究終了まで、平均血清中25−ヒドロキシビタミンDは、30ng/mL未満であり、治療前ベースラインに比べてほぼ11ng/mLだけ高い。本研究によるデータは、本明細書に記載のように製剤化され、1日30μgの投与量で20日間投与される600μgの25−ヒドロキシビタミンD3の投与は、25−ジドロキシビタミンDの低い血清中濃度を最適濃度まで戻す上で、NKFおよび経口ビタミンD補充療法に関する他の指導的専門家によって現在推奨されているような、単回投与で投与される50,000IUのエルゴカルシフェロールまたはコレカルシフェロールのどちらかの即放性製剤に比べて実質上より効果的であることを立証している。
ステージ4のCKD、およびビタミンDの不足に付随する二次性副甲状腺機能亢進症を有する患者での効力研究
血清中総25−ヒドロキシビタミンDを最適濃度(>30ng/mL)まで戻す上での経口即放性および調節放出性25−ヒドロキシビタミンD3の有効性を、ステージ4のCKD、およびビタミンDの不足に付随する二次性副甲状腺機能亢進症を有する成人の男性および女性患者での6カ月間の研究で調べる。研究では2種の製剤を使用する。製剤の1つ(製剤#1)は、調節放出性製剤中に40μgの25−ヒドロキシビタミンD3を含有する軟質ゼラチンカプセルである。第2の製剤(製剤#2)は、即放性製剤中に40μgの25−ヒドロキシビタミンD3を含有する軟質ゼラチンカプセルである。本研究には、全部で100名の対象が参加し、そのすべては、30〜70歳であり、15〜29ng/mL(両端を含む)の血清中25−ヒドロキシビタミンD濃度、および登録時点で最新のK/DOQIガイドライン中に発表されている目標濃度を超える血清中全分子副甲状腺ホルモン(iPTH)濃度を有する。すべての対象は、研究開始前の60日間および続いて研究終了までの他のビタミンDサプリメントの摂取、ならびに特に問題となるほどの総曝露を絶つ。すべての対象は、製剤#1または製剤#2のどちらかの2カプセルで毎日の投与を開始する。血清中総25−ヒドロキシビタミンDを隔週間隔で測定し、血清中iPTHを3カ月置きの間隔で測定する。1カ月後、両製剤の1日当たり投与量を、血清中総25−ヒドロキシビタミンDが50〜90ng/mLである患者では変えないで維持し、血清中総25−ヒドロキシビタミンDが50ng/mL未満である患者では1カプセルだけ増やし、血清中総25−ヒドロキシビタミンDが90ng/mLを超える患者では1日1カプセルだけ減らす。血清中総25−ヒドロキシビタミンDを50〜90ng/mLに維持するために、1日当たり投与量のさらなる調整を行う。製剤#1および#2の投与は、両方とも、高カルシウム血症、高カルシウム尿症および高リン血症を発症しないとの条件で期限を決めずに継続されるが、その場合には、投与量の適切な調整がなされる。6カ月後、対象の血清中総25−ヒドロキシビタミンD濃度は、製剤#1を用いる治療で50〜90ng/mLで安定したままであることが見出され、血清中iPTHは、K/DOQIガイドライン中に発表されている目標と一致した濃度で安定したままであることが見出される。高カルシウム血症、高カルシウム尿症および高リン血症の発症は、いったん安定した投与が達成されると稀である。対照的に、6カ月後、対象の血清中総25−ヒドロキシビタミンD濃度は、製剤#2を用いる治療で50〜90ng/mLで安定したままであることが見出されず、血清中iPTHは、K/DOQIガイドライン中に発表されている目標と一致した濃度に到達しない。高カルシウム血症、高カルシウム尿症および高リン血症の発症は、実在する。
Claims (64)
- 製剤を摂取する対象の消化管中でのビタミンD化合物の制御放出のための製剤であって、ワックス状制御放出性担体物質、類脂質性物質、ビタミンD化合物用油性ビヒクル、およびビタミンD化合物を含む固体または半固体のワックス状混合物を含有する製剤。
- 前記混合物が、室温で固体または半固体、体温で固体、半固体または液体である、請求項1に記載の製剤。
- 前記混合物が、室温で固体または半固体、体温で半固体または液体である、請求項1または2に記載の製剤。
- 前記ワックス状制御放出性担体物質が、非消化性ワックスを含む、請求項1から3までのいずれか1項に記載の製剤。
- 前記非消化性ワックスが、パラフィンワックスを含む、請求項4に記載の製剤。
- 前記ワックス状制御放出性担体物質が、5wt%〜35wt%の範囲の量で存在する、請求項1から5までのいずれか1項に記載の製剤。
- 前記ワックス状制御放出性担体物質が、5wt%〜30wt%の範囲の量で存在する、請求項6に記載の製剤。
- 前記類脂質性物質が、約13〜約18の範囲のHLBを有する、請求項1から7までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、7未満のHLBを有する乳化剤である、請求項1から8までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、混合脂肪酸モノグリセリド;混合脂肪酸ジグリセリド;脂肪酸のモノグリセリドとジグリセリドとの混合物;親油性ポリグリセロールエステル;モノオレイン酸グリセリル、ジオレイン酸グリセリル、モノステアリン酸グリセリル、ジステアリン酸グリセリル、モノパルミチン酸グリセリルおよびジパルミチン酸グリセリルを含めたグリセロールエステル;脂肪酸のグリセリル−ラクトエステル;モノパルミチン酸プロピレングリコール、モノステアリン酸プロピレングリコールおよびモノオレイン酸プロピレングリコールを含めたプロピレングリコールエステル;モノステアリン酸ソルビタン、セスキオレイン酸ソルビタンを含めたソルビタンエステル;ステアリン酸、パルミチン酸およびオレイン酸を含めた脂肪酸およびそれらの石鹸;ならびにこれらの混合物;モノオレイン酸グリセリル、ジオレイン酸グリセリル、モノステアリン酸グリセリル、ジステアリン酸グリセリル、モノパルミチン酸グリセリルおよびジパルミチン酸グリセリル;脂肪酸のグリセリル−ラクトエステル;モノパルミチン酸プロピレングリコール、モノステアリン酸プロピレングリコールおよびモノオレイン酸プロピレングリコールを含めたプロピレングリコールエステル;モノステアリン酸ソルビタン、セスキオレイン酸ソルビタンを含めたソルビタンエステル;ステアリン酸、パルミチン酸およびオレイン酸を含めた脂肪酸およびそれらの石鹸;ならびにこれらの混合物からなる群から選択される、請求項9に記載の製剤。
- 前記類脂質性物質が、グリセリドおよびその誘導体から選択される、請求項1から10までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、カプリロカプロイルマクロゴールグリセリドから選択される、請求項1から11までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、ポリグリコール化グリセリドを含む、請求項1から12までのいずれか1項に記載に製剤。
- 前記ポリグリコール化グリセリドが、約44℃の融点および約14のHLBを特徴とする、請求項13に記載の製剤。
- 前記類脂質性物質が、カプリロカプロイルマクロゴール−8−グリセリドを含む、請求項1から14までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、7未満のHLBを有する親油性乳化剤と好ましくは13〜18のHLB値を有する吸収増強剤との混合物を含む、請求項1から15までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、5wt%〜60wt%の範囲の量で存在する、請求項1から16までのいずれか1項に記載の製剤。
- 前記類脂質性物質が、20wt%〜60wt%の範囲の量で存在する、請求項17に記載の製剤。
- 前記油性ビヒクルが、非消化性オイルを含む、請求項1から18までのいずれか1項に記載の製剤。
- 前記油性ビヒクルが、ミネラルオイル、スクアレン、およびこれらの混合物からなる群から選択される、請求項19に記載の製剤。
- 前記油性ビヒクルが、製剤の約10wt%〜約50wt%を構成する、請求項1から20までのいずれか1項に記載の製剤。
- 前記油性ビヒクルが、製剤の約20wt%〜約45wt%を構成する、請求項21に記載の製剤。
- ビタミンD化合物の制御放出性経口投与製剤であって、薬理学的に活性な量のビタミンD化合物、ならびに(a)ボーラスIV注射によって投与される等価量のビタミンD化合物、および(b)有効量の放出調節剤を除外した同様の剤形のどちらかまたは両方と比較して、投与間隔内でのビタミンD化合物の最大血清中濃度(Cmax)を低下させるように、かつ/またはビタミンD化合物の血漿中濃度が投与後の投与間隔内でその最大値に到達する時間(Tmax)を増大させるように、かつ/または投与後24時間以内でのビタミンD化合物の最大血清中濃度の投与24時間後濃度に対する比率(Cmax24hr/C24hr)を低下させるように、剤形からのビタミンD化合物の放出速度を調節するのに有効な量の放出調節剤を含有する制御放出性経口投与製剤。
- 前記剤形が、低下したCmaxおよび増大したTmaxの両方を特徴とする、請求項23に記載の製剤。
- Cmaxの前記低下が、少なくとも20%である、請求項23または24に記載の製剤。
- Cmaxの前記低下が、少なくとも30%である、請求項25に記載の製剤。
- Cmaxの前記低下が、少なくとも40%である、請求項26に記載の製剤。
- Cmaxの前記低下が、少なくとも50%である、請求項27に記載の製剤。
- Cmaxの前記低下が、少なくとも60%である、請求項28に記載の製剤。
- Cmaxの前記低下が、少なくとも70%である、請求項29に記載の製剤。
- Cmaxの前記低下が、少なくとも80%である、請求項30に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも20%である、請求項23または24に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも30%である、請求項32に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも40%である、請求項33に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも50%である、請求項34に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも60%である、請求項35に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも70%である、請求項36に記載の製剤。
- Cmax24hr/C24hrの前記低下が、少なくとも80%である、請求項37に記載の製剤。
- 前記ビタミンD化合物が、25−ヒドロキシビタミンD3を含む、請求項1から38までのいずれか1項に記載の製剤。
- 単位投与量当たり1μg〜100μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項39に記載の製剤。
- 単位投与量当たり5μg〜90μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項40に記載の製剤。
- 単位投与量当たり30μg〜80μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項41に記載の製剤。
- 単位投与量当たり30μg〜60μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項42に記載の製剤。
- 単位投与量当たり20μg〜60μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項43に記載の製剤。
- 単位投与量当たり35μg〜50μgの範囲の量で存在する25−ヒドロキシビタミンD3を含有する、請求項44に記載の製剤。
- 単位投与量当たり40μgの量で存在する25−ヒドロキシビタミンD3を含有する、請求項40に記載の製剤。
- 崩壊剤を本質的に含有しない、請求項1から46までのいずれか1項に記載の製剤。
- 投与間隔内でのビタミンD化合物の最大血清中濃度(Cmax)が、ボーラスIV注射および/または即放性経口剤形によって投与される等価量のビタミンD化合物に対するCmaxと比較して低下するような制御放出によって患者にビタミンD化合物を投与する方法。
- 前記低下が、少なくとも20%である、請求項48に記載の方法。
- ビタミンD化合物の投与後24時間以内での最大血清中濃度の投与24時間後濃度に対する比率(Cmax24hr/C24hr)が、ボーラスIV注射および/または即放性経口剤形によって投与される等価量のビタミンD化合物に比較して低下するような制御放出によって患者にビタミンD化合物を投与する方法。
- 前記低下が、少なくとも20%である、請求項50に記載の方法。
- ビタミンD化合物の排出半減期(t1/2)が、ボーラスIV注射および/または相当する即放性経口剤形によって投与される等価量のビタミンD化合物に対するt1/2に比較して増大するような制御放出によって患者にビタミンD化合物を投与する方法。
- 前記増大が、少なくとも25%である、請求項52に記載の方法。
- ビタミンD化合物の血漿中濃度が、投与後の投与間隔内でその最大値に到達する時間(Tmax)が、ボーラスIV注射および/または相当する即放性経口剤形によって投与される等価量のビタミンD化合物に対するTmaxに比較して増大するような制御放出によって患者にビタミンD化合物を投与する方法。
- 前記縮小が、少なくとも25%である、請求項54に記載の方法。
- 前記ビタミンD化合物が、25−ヒドロキシビタミンD3を含む、請求項48から55までのいずれか1項に記載の方法。
- 25−ヒドロキシビタミンD3を1日につき1〜100μgの範囲の量でヒト患者に長期間投与することを含む、請求項56に記載の方法。
- 前記長期間が、少なくとも1カ月である、請求項57に記載の方法。
- 前記ヒト患者のビタミンDが欠乏している、請求項48から58までのいずれか1項に記載の方法。
- 患者の血清中25(OH)D濃度を少なくとも30ng/mLまで上昇させるために、ヒト患者に25−ヒドロキシビタミンD3を投与することを含む、請求項48から59までのいずれか1項に記載の方法。
- 前記ヒト患者のビタミンDが充足している、請求項48から58までのいずれか1項に記載の方法。
- 患者の血清中25(OH)D濃度が30ng/mL未満に降下することを予防するために、ヒト患者に25−ヒドロキシビタミンD3を投与することを含む、請求項48から61までのいずれか1項に記載の方法。
- 前記ヒト患者が、ビタミンD欠乏症に付随した二次性副甲状腺機能亢進症を有する、請求項48から60までのいずれか1項に記載の方法。
- 前記ヒト患者に25−ヒドロキシビタミンD3を投与して患者の血清中25(OH)D濃度を少なくとも30ng/mLまで上昇させることによってヒト患者の高められたPTHを低下させることを含む、請求項63に記載の方法。
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