JP2018517717A - エステトロール成分を含有する口腔内崩壊性投与単位 - Google Patents
エステトロール成分を含有する口腔内崩壊性投与単位 Download PDFInfo
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- JP2018517717A JP2018517717A JP2017564097A JP2017564097A JP2018517717A JP 2018517717 A JP2018517717 A JP 2018517717A JP 2017564097 A JP2017564097 A JP 2017564097A JP 2017564097 A JP2017564097 A JP 2017564097A JP 2018517717 A JP2018517717 A JP 2018517717A
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- Prior art keywords
- dosage unit
- estetrol
- weight
- orally disintegrating
- particles
- Prior art date
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- Granted
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- 229950009589 estetrol Drugs 0.000 title claims abstract description 180
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- 239000007787 solid Substances 0.000 claims abstract description 77
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- 238000000034 method Methods 0.000 claims description 41
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
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Abstract
【選択図】なし
Description
上記エステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る。
国際公開第2002/094275号は、女性のリビドーを増強する方法におけるエステトロールの使用について記載されており、前記方法は、前記女性に有効量のエステトロールを投与することを含む。経口投与は適切な投与様式として言及されている。この特許出願は、国際公開第2002/094276号と同じエステトロール錠剤について記載されている。
国際公開第2003/041718号は、哺乳動物に対するホルモン補充法におけるエステトロールの使用について記載されており、前記方法は、哺乳動物に、低エストロゲン症の症状を予防又は治療するために有効な量のエステトロール及びプロゲストゲン成分を経口投与することを含む。この特許出願は、国際公開第2002/094279号と同じエステトロール錠剤について記載されている。
上記エステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であって、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
上記エステトロール粒子を1種又は複数の薬学的に許容される成分を混合することによって乾燥混合物を調製するステップ、及び
上記乾燥混合物を固形投与単位に圧縮するステップ
を含む方法によって入手可能である。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であって、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
上記エステトロール粒子1重量部を1種又は複数の薬学的に許容される賦形剤2〜1,000重量部と混合することによって乾燥混合物を調製するステップ、及び
上記乾燥混合物を固形投与単位に圧縮するステップ
を含む。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る前記投与単位であって、
上記エステトロール成分を少なくとも100μg含有する上記固形投与単位に関し;
ここで、前記固形投与単位は:
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であって、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
上記エステトロール粒子を1種又は複数の薬学的に許容される賦形剤と混合することによって乾燥混合物を調製するステップ、及び
上記乾燥混合物を固形投与単位に圧縮するステップ
を含む方法によって得られる。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であり、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
上記エステトロール粒子1重量部を1種又は複数の薬学的に許容される賦形剤2〜1,000重量部と混合することによって乾燥混合物を調製するステップ、及び
上記乾燥混合物を固形投与単位に圧縮するステップ
を含む、前記方法に関する。
下記溶出試験は、口腔内崩壊性投与単位の溶出挙動を試験するために適用することができる。
パドル及びバスケット溶出試験器バンケルVK7010(VanKel VK7010)又はVK7025、オートサンプラーVK8000、1000mL溶出試験器用ベッセル、及び多孔性ミクロンフィルター(35ピン)
10,000mLのメスフラスコに脱イオン水(demineralised water)9,000mLを移す。
68.05gのKH2PO4及び8.96gのNaOHを加え、すべてが溶解するまで上記溶液を撹拌する。
上記溶液を混合し、必要であれば、NaOH又はリン酸を用いてpHを6.8に調整し、脱イオン水を用いて体積を調整する。
溶出媒体900mLをパドル装置の各ベッセルに移す。
装置を組み立て、上記媒体を37±0.5℃に加温し、温度計を取り外す。
パドルの回転を開始する前に6個のベッセルの底にそれぞれ1個の錠剤を置く。
直ちにパドルの回転を開始する。
50rpmの撹拌速度を用いる。
1.15gのNH4H2PO4(10mM)を脱イオン水1,000mLに移して溶解し、リン酸を用いてpHを3.0に調整する。
クォータナリ溶媒送達システム、容量可変インジェクター、温度制御オートサンプラー、カラム恒温槽、及びフォトダイオードアレイ検出器2996(すべてWaters)から成るアライアンス2695(Alliance2695)分離モジュール
分析カラム:シンメトリーC18(Symmetry C18)、3.9×150mm、dp=5μm(Waters製)
ガードカラム:セキュリティーガード(Security guard)カラムC18、4x3mm(Phenomenex)
流量:1.0mL/分
検出:UV@280nm
カラム温度:30℃
オートサンプラー温度:10℃
注入量:100μL
実行時間:12分
溶出試験は3回実施する。
エステトロール一水和物の粒径分布は、マルバーンマスターサイザーマイクロプラス(MALVERN MASTERSIZER MICROPLUS)レーザー粒径分析器を用いて実施する。
エステトロール一水和物1g及びトリオレイン酸ソルビタン1gをフラスコ内に量り取る。
n−ヘキサン1Lを加え、室温で少なくとも1時間混合する。
0.45μmフィルターを通して濾過する。
サンプル100mgを25mLビーカーに入れる。
分散媒を数滴加える。
ガラス棒で慎重に混合し、粉末を十分に懸濁させる。
分散媒10mLを加える。
サンプル分散ユニットの速度3000〜3500rpmで分析を実施する。
粒径測定は、同じ分散を用いて3回実施する。最終的な結果は、3回の検出結果を平均して得られる。
舌下錠は、下記の手順によって調製する。
舌下錠は、下記の手順によって調製する。
5種の異なる舌下錠のセット(製剤処方A〜E)は、下記の手順及び図1に示される手順によって調製した。
無作為化、非盲検、二期間、クロスオーバー、薬物動態試験を実施し、100mgの錠剤1個で投与されたエステトロール10mgの舌下バイオアベイラビリティと、エステトロール10mgを含有する83mgの錠剤に含有されたエステトロールの経口アベイラビリティを比較した。これらの錠剤は、絶食状態の女性健常者に舌下及び経口投与された。
Claims (26)
- 重量が30〜1,000mgの間である口腔内崩壊性固形医薬投与単位であって:
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成り、
前記エステトロール成分を少なくとも100μg含有し、
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であって、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
前記エステトロール粒子を1種又は複数の薬学的に許容される賦形剤と混合することによって乾燥混合物を調製するステップ、及び
前記乾燥混合物を固形投与単位に圧縮するステップ
を含む方法によって得られる、口腔内崩壊性固形医薬投与単位。 - 前記投与単位の重量が40〜500mgの間である、請求項1に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が前記エステトロール成分を0.5〜25重量%含有する、請求項1又は2に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が前記エステトロール成分を0.3〜100mg含有する、請求項1〜3のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記エステトロール成分がエステトロールである、請求項1〜4のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記エステトロール粒子の体積中位径が3〜35μmである、請求項1〜5のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が、マルトース、フルクトース、スクロース、ラクトース、グルコース、ガラクトース、トレハロース、キシリトール、ソルビトール、エリスリトール、マルチトール、マンニトール、イソマルト、微結晶セルロース、カルシウム塩、及びその組合せから選択される充填剤を50〜99.5体重%含有する、請求項1〜6のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が、ラクトース、キシリトール、ソルビトール、エリスリトール、マンニトール、微結晶セルロース、及びその組合せから選択される充填剤を50〜99.5体重%含有する、請求項7に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が、マンニトール、キシリトール、及びその組合せから選択される糖アルコールを少なくとも20重量%含有する、請求項7又は8に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が、加工デンプン、架橋ポリビニルピロリドン、クロスカルメロース、及びその組合せから選択される崩壊剤を0.1〜20重量%含有する、請求項1〜9のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が微結晶セルロースを0〜60重量%含有する、請求項1〜10のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 前記投与単位が、フマル酸ステアリルナトリウム、ステアリン酸マグネシウム、ステアリン酸、ラウリル硫酸ナトリウム、タルク、ポリエチレングリコール、ステアリン酸カルシウム、及びその混合物から選択される滑沢剤を0.1〜2重量%含有する、請求項1〜11のいずれか一項に記載の口腔内崩壊性固形医薬投与単位。
- 医学的治療における使用又は女性ホルモン補充療法における使用であって、前記投与単位を舌下、頬側、又は唇下投与することを含む前記使用のための、請求項1〜12のいずれか一項に記載の固形投与単位。
- 請求項13に記載の使用であって、少なくとも1週間の期間に1日1回投与することを含む前記使用のための固形投与単位。
- 女性の避妊の方法であって、請求項1〜12のいずれか一項に記載の投与単位を舌下、頬側、又は唇下投与することを含む前記方法。
- 前記方法が少なくとも1週間の期間に1日1回投与することを含む、請求項15に記載の方法。
- 請求項1〜12のいずれか一項に記載の固形投与単位を製造する方法であって:
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子であって、体積中位径が2μm〜50μmの範囲内である前記エステトロール粒子を形成するステップ、
前記エステトロール粒子1重量部を1種又は複数の薬学的に許容される賦形剤2〜1,000重量部と混合することによって乾燥混合物を調製するステップ、及び
前記乾燥混合物を固形投与単位に圧縮するステップ
を含む、前記方法。 - 前記方法が、前記エステトロール粒子と前記1種又は複数の薬学的に許容される賦形剤の混合中又は混合後に、液体溶媒を加えるステップを含まない、請求項17に記載の方法。
- 前記エステトロール粒子の体積中位径が3〜35μmである、請求項17又は18に記載の方法。
- 前記乾燥混合物が、マルトース、フルクトース、スクロース、ラクトース、グルコース、ガラクトース、トレハロース、キシリトール、ソルビトール、エリスリトール、マルチトール、マンニトール、イソマルト、微結晶セルロース、カルシウム塩、及びその組合せから選択される充填剤を50〜99.5重量%含有する、請求項17〜19のいずれか一項に記載の方法。
- 前記投与単位が、ラクトース、キシリトール、ソルビトール、エリスリトール、マンニトール、微結晶セルロース、及びその組合せから選択される充填剤を50〜99.5重量%含有する、請求項20に記載の方法。
- 前記乾燥混合物が、マンニトール、キシリトール、及びその組合せから選択される糖アルコールを少なくとも20重量%含有する、請求項20又は21に記載の方法。
- 前記乾燥混合物が、加工デンプン、架橋ポリビニルピロリドン、クロスカルメロース、及びその組合せから選択される崩壊剤を0.1〜20重量%含有する、請求項17〜22のいずれか一項に記載の方法。
- 前記投与単位が微結晶セルロースを0〜60重量%含有する、請求項17〜23のいずれか一項に記載の方法。
- 前記乾燥混合物が、フマル酸ステアリルナトリウム、ステアリン酸マグネシウム、ステアリン酸、ラウリル硫酸ナトリウム、タルク、ポリエチレングリコール、ステアリン酸カルシウム、及びその混合物から選択される滑沢剤を0.1〜2重量%含有する、請求項17〜24のいずれか一項に記載の方法。
- 前記固形投与単位が直接圧縮によって形成される、請求項17〜25のいずれか一項に記載の方法。
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