JP5931042B2 - 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 - 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 Download PDFInfo
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- JP5931042B2 JP5931042B2 JP2013241875A JP2013241875A JP5931042B2 JP 5931042 B2 JP5931042 B2 JP 5931042B2 JP 2013241875 A JP2013241875 A JP 2013241875A JP 2013241875 A JP2013241875 A JP 2013241875A JP 5931042 B2 JP5931042 B2 JP 5931042B2
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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。
現在の経口サプリメントを摂取した後の管腔内ビタミンD濃度の急増は、局所腸細胞中のビタミンDおよびプロホルモン濃度を直接的に押し上げ、それによって、小腸中でのカルシウムおよびリンの代謝に関する「初回通過」効果を発揮することができる。
それは、異常に高められた血中PTH濃度によって特徴付けられ、早期の発見および治療が欠如すると、副甲状腺過形成および一連の代謝性骨疾患が付随するようになる。それは、慢性腎臓病(CDK)の広く知られた合併症であり、CKDが進行するにつれて発生率が上昇する。二次性副甲状腺機能亢進症は、健康な腎臓を有する個体でも、十分なビタミンDの供給を妨げる環境、文化または食事因子によって発症する場合がある。
驚くべきことではないが、ほとんどのCKD患者は、二次性副甲状腺機能亢進症を発症する。残念ながら、CKDにおける二次性副甲状腺機能亢進症の早期の発見および治療は、まれであり、ましてや予防は稀有である。
ステージ5のCKDを有する患者において、血漿中iPTHの過剰抑制は、該患者が、100pg/mL未満の血漿中iPTH濃度を有する場合に見出される。
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 (40)
- ヒト患者における慢性腎臓病(CKD)ステージ3またはステージ4に付随した二次性副甲状腺機能亢進症を治療するための医薬組成物であって、ヒト患者の血清中副甲状腺ホルモン濃度を少なくとも30%低下させるが、血清中総25−ヒドロキシビタミンD濃度を安全に上昇させるのに有効な量の25−ヒドロキシビタミンDの制御放出性経口剤形を含み、制御放出性経口剤形中の25−ヒドロキシビタミンDの量が単位用量当たり1mcg〜1000mcgの範囲である、医薬組成物。
- ヒト患者がビタミンD不足またはビタミンD欠乏症である、請求項1に記載の医薬組成物。
- 25−ヒドロキシビタミンDの制御放出性経口剤形の前記有効量がヒト患者の血清中総25−ヒドロキシビタミンD濃度を少なくとも30ng/mLまで上昇させるのに有効である、請求項2に記載の医薬組成物。
- 25−ヒドロキシビタミンDの制御放出性経口剤形の前記有効量がヒト患者の血清中総25−ヒドロキシビタミンD濃度を50ng/mL〜90ng/mLの範囲内の値に上昇させるのに有効である、請求項3に記載の医薬組成物。
- 前記組成物がヒト患者の血漿中全分子副甲状腺ホルモン濃度をCKDステージの目標範囲に低下させるために投与される、請求項1に記載の医薬組成物。
- 25−ヒドロキシビタミンDが、25−ヒドロキシビタミンD2、25−ヒドロキシビタミンD3並びに25−ヒドロキシビタミンD2および25−ヒドロキシビタミンD3の組み合わせからなる群より選ばれる、請求項1に記載の医薬組成物。
- 25−ヒドロキシビタミンDが25−ヒドロキシビタミンD3である、請求項6に記載の医薬組成物。
- 1日1回のスケジュールで投与するための、請求項1に記載の医薬組成物。
- 日用量が1mcg〜1000mcgの範囲である、請求項8に記載の医薬組成物。
- 25−ヒドロキシビタミンDの日用量が1mcg〜1000mcgの範囲である、請求項1に記載の医薬組成物。
- 副甲状腺機能亢進症を治療するための、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化合物の血清中濃度における最大変化を減らし、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し、ビタミンD化合物が25−ヒドロキシビタミンD2、25−ヒドロキシビタミンD3またはその組み合わせからなる群より選ばれる化合物を含む、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11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11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11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14に記載の製剤。
- Tmaxの前記増大が少なくとも100%である、請求項14に記載の製剤。
- ビタミンD化合物の血清中濃度における最大変化の前記減少が少なくとも20%である、請求項11に記載の製剤。
- ビタミンD化合物の血清中濃度における最大変化の前記減少が少なくとも70%である、請求項17に記載の製剤。
- Tmaxの前記増大が少なくとも100%である、請求項17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11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20に記載の製剤。
- Tmaxの前記増大が少なくとも100%である、請求項20に記載の製剤。
- Tmaxの前記増大が少なくとも100%である、請求項11に記載の製剤。
- Tmaxの前記増大が少なくとも150%である、請求項23に記載の製剤。
- 副甲状腺機能亢進症を治療するための制御放出性の25−ヒドロキシビタミンDを含む医薬組成物であって、(a)単位用量当たり1mcg〜1000mcgの投与量での制御放出製剤の経口送達によって、または、(b)1日につき1〜100μgの投与量での静脈内送達によって、25−ヒドロキシビタミンDが投与される、医薬組成物。
- 副甲状腺機能亢進症が二次性副甲状腺機能亢進症であり、任意で副甲状腺機能亢進症が慢性腎臓病(ステージ3、4または5)に付随した副甲状腺機能亢進症である、請求項25に記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 25−ヒドロキシビタミンDが経口投与される、請求項25または26に記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 血清中副甲状腺ホルモン濃度を低下させるために25−ヒドロキシビタミンDが制御放出性剤形で投与される、請求項27に記載の25−ヒドロキシビタミンDを含む医薬組成物。
- ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のCmaxと比較して、Cmaxを任意で少なくとも20%、さらに任意で少なくとも70%低下させるために、剤形が投与される、請求項28に記載の25−ヒドロキシビタミンDを含む医薬組成物。
- ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のTmaxと比較して、Tmaxを任意で少なくとも100%、さらに任意で少なくとも150%増加させるために、剤形が投与される、請求項28または29に記載の25−ヒドロキシビタミンDを含む医薬組成物。
- ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のCmax24hr/C24hrと比較して、Cmax24hr/C24hrの比率を任意で少なくとも20%、さらに任意で少なくとも30%低下させるために、剤形が投与される、請求項28〜30のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物の血清中濃度の最大変化と比較して、25−ヒドロキシビタミンD化合物の血清中濃度の最大変化を任意で少なくとも20%、さらに任意で少なくとも70%低下させるために、剤形が投与される、請求項28〜31のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 血清中25−ヒドロキシビタミンD濃度を、少なくとも30ng/mLの量で、任意で50〜90ng/mLの範囲で維持するために、剤形が投与される、請求項28〜32のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- CKD患者の血清中副甲状腺ホルモン濃度をCKDステージ特異的な目標範囲まで低減させるために、剤形が投与される、請求項28〜33のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 剤形が1日につき1回の計画で投与される、請求項28〜34のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 高カルシウム血症を回避しながら副甲状腺機能亢進症を治療するために、剤形が投与される、請求項28〜35のいずれかに記載の25−ヒドロキシビタミンDを含む医薬組成物。
- 副甲状腺機能亢進症を治療するための、薬理学的に活性な量の25−ヒドロキシビタミンDおよび放出調節剤を含む25−ヒドロキシビタミンDの制御放出性剤形であって、
放出調節剤が、
(a)ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のCmaxと比較してCmaxを低下させるように、剤形からの25−ヒドロキシビタミンD化合物の放出速度を制御し、
または
(b)ボーラスIV注射および/または即放性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のTmaxと比較してTmaxを増大させるように剤形からの25−ヒドロキシビタミンD化合物の放出速度を制御し、
または、
(c)ボーラスIV注射および/または即放出性経口剤形で投与される等価量の25−ヒドロキシビタミンD化合物のCmax24hr/C24hrと比較してCmax24hr/C24hrの比率を低減させるように剤形からの25−ヒドロキシビタミンD化合物の放出速度を制御し、かつ、
経口投与される、制御放出性剤形。 - (i)放出調節剤が選択肢(a)に従い、Cmaxを少なくとも20%、さらに任意で少なくとも70%低下させるか、
(ii)放出調節剤が選択肢(b)に従い、Tmaxを少なくとも100%、さらに任意で少なくとも150%増大させるか、
(iii)放出調節剤が選択肢(c)に従い、Cmax24hr/C24hrを少なくとも20%、さらに任意で少なくとも30%低下させる、請求項37に記載の制御放出性剤形。 - 剤形が1〜100μgの25−ヒドロキシビタミンDを含む、請求項37または38に記載の制御放出性剤形。
- (a)剤形が25−ヒドロキシビタミンD2、25−ヒドロキシビタミンD3、あるいは25−ヒドロキシビタミンD2および25−ヒドロキシビタミンD3の組合せを含む、または、
(b)剤形が25−ヒドロキシビタミンD3を含む、請求項37〜39のいずれかに記載の制御放出性剤形。
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