JP6097803B2 - 経口テストステロンエステル配合剤およびそれを含むテストステロン欠損を処置する方法 - Google Patents
経口テストステロンエステル配合剤およびそれを含むテストステロン欠損を処置する方法 Download PDFInfo
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- JP6097803B2 JP6097803B2 JP2015184441A JP2015184441A JP6097803B2 JP 6097803 B2 JP6097803 B2 JP 6097803B2 JP 2015184441 A JP2015184441 A JP 2015184441A JP 2015184441 A JP2015184441 A JP 2015184441A JP 6097803 B2 JP6097803 B2 JP 6097803B2
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Description
本発明は、一般に、テストステロン欠損の処置のためのテストステロンエステルの経口配合剤に関する。より詳細には本発明は、吸収および薬物動態を増強および長期化させるテストステロンウンデカノエート(TU)を含む医薬組成物に関する。
テストステロン(T)は、精巣の間質細胞内で産生される主要な男性ホルモンであり、男性性器の正常な成長、発達および維持、ならびに第二次性徴(例えば、声の低音化、筋肉の発達、ひげなど)を担う。テストステロンは、成人の生活全般を通して、精巣ならびにその付属構造である前立腺および精嚢の適切な機能のため、幸福感のため、そして性欲、勃起能力の維持のために必要である。
本発明の一実施形態において、親水性界面活性剤の合計に対する親油性界面活性剤の合計の比(w/w)が約6:1〜3.5:1の範囲に入る、少なくとも1種の親油性界面活性剤および少なくとも1種の親水性界面活性剤を含む担体中に可溶化されたテストステロンウンデカノエートを含み、1日1または2回の経口投与により約300〜約1100ng/dLの範囲内に入る定常状態の平均血清テストステロン濃度を提供する、経口医薬組成物が提供される。その医薬組成物は、食事と一緒に投与されると、2500ng/dLを超えない、好ましくは1800ng/dLを超えない、最も好ましくは1500ng/dLを超えないCmaxを提供する。
(a)15〜25重量%の可溶化テストステロンウンデカノエート;
(b)12〜18重量%の少なくとも1種の親水性界面活性剤;
(c)50〜65重量%の少なくとも1種の親油性界面活性剤;
(d)10〜15重量%のルリジサ油とペパーミント油との混合物、
を含み、一般には一価アルコール、具体的にはエタノールを含まなくてもよく、必要とする対象への経口投与により、約10時間〜約18時間の範囲内に入る血清テストステロン半減期(T1/2)を生じる、医薬組成物が提供される。Cremophor RH40は、好ましい親水性界面活性剤であり、好ましい親油性界面活性剤は、オレイン酸である。ルリジサ油およびペパーミント油は、両者とも考慮される親油性界面活性剤である。
(a)18〜22重量%の可溶化テストステロンウンデカノエート;
(b)15〜17重量%の少なくとも1種の親水性界面活性剤;
(c)50〜55重量%の少なくとも1種の親油性界面活性剤;および
(d)10〜15重量%のルリジサ油とペパーミント油との混合物、
を含む。ペパーミント油に対するルリジサ油の比は、8:1〜3:1、好ましくは6:1〜5:1、最も好ましくは5:1〜4:1の範囲内であってもよい。Cremophor RH40に加えて、Solutol HS−15、Tween 80およびTPGSが、好ましい親水性界面活性剤であり、オレイン酸に加えて、モノオレイン酸グリセロール、ラウリン酸プロピレングリコールおよびCapmul MCMが、好ましい親油性界面活性剤である。2種以上の親油性界面活性剤と2種以上の親水性界面活性剤との組み合わせも、企図される。
(a)15〜25重量%の可溶化テストステロンウンデカノエート;
(b)12〜18重量%の1種以上の親水性界面活性剤;
(c)50〜65重量%の1種以上の親油性界面活性剤;
(d)10〜15重量%のルリジサ油とペパーミント油との混合物、
を含み、エタノールを含まず、1日1または2回の経口投与により、対象において約300〜約1100ng/dLの範囲内に入る平均の(または平均)定常状態血清テストステロン濃度Caveを生じる医薬組成物の効果的量を、性腺機能不全の対象へ経口投与することを含む、テストステロン欠損を処置する方法が提供される。その組成物は、場合により、脂肪量が約15重量%〜約25重量%またはそれを超える範囲の食事と一緒に投与してもよい。その方法によれば、以下の薬物動態パラメータの任意の1つまたは全てを、対象において実現してもよい:
(a)対象において900〜1100ng/dLの血清テストステロンCmax;
(b)実質的に存在しない日中のテストステロン薬物動態変動;
(c)組成物投与後3〜7時間目の血清Tmax;および
(d)反復投与により観察される、実質的に降下しない定常状態血清テストステロン応答。
本発明は、性腺機能不全の男性へ1日2回以下の回数投与した場合に、米国食品医薬品局により許容されなければ不適切と見なされる高いCmax値を回避しながら、所望の「正常な」または性腺機能が正常な範囲(即ち、約300〜1100ng/dL)に入る、そのような男性の定常状態血清テストステロンレベル(濃度)を提供する、TUを含む経口医薬組成物を提供する。例えば、処置された対象の85%未満が、1500ng/dL以上のCmax値を有しうること、そしてどの対象も2500ng/dLを超えるCmax値を有しえないことが、FDA認可ガイドラインに述べられている。処置された対象の5%未満が、1800〜2500ng/dLの範囲内に入るCmax値を有する可能性がある。その上、本発明の配合剤は、自己乳化性薬物送達システム(SEDDS)になるように設計されているため、胃腸管内の腸液と混合されるとTU含有エマルジョン(または分散液)が形成される。
が挙げられる。
が挙げられる。
親水性界面活性剤:10〜20%、より好ましくは12〜18%、最も好ましくは15〜17%。
親油性界面活性剤:50〜70%、より好ましくは50〜65%、最も好ましくは50〜55%。
他の油:5〜15%、より好ましくは7〜15%、最も好ましくは10〜13%。
薬物:10〜30%、より好ましくは15〜25%、最も好ましくは18〜22%。
2 Swerdloff, RS, et a (2000). Long−term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J. Clin. Endocrinol. Metab. 85: 4500−4510.
3 Wang, C et al (2004). Long−term testosterone gel (AndroGel(登録商標) treatment maintains beneficial effects on sexual function and mood, lean and fat mass and bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab. 89:2085−2098.
4 Houwing, NS et al (2003). Pharmacokinetic study in women of three different doses of a new formulation of oral testosterone undecanoate, Andriol Testocaps. Pharmcotherapy: 23: 1257−1265.
5 Gooren, LJG (1994). A ten−year safety study of the oral androgen testosterone undecanoate. J. Androl. 15: 212−215.
配合剤Bを、性腺機能不全の男性への1日1回または2回投与による1日薬物動態プロファイルについて試験した。試験は、非盲検1日投与逐次(sequential)クロスオーバー薬物動態試験として設定した。性腺機能不全の男性12名を、インフォームドコンセントに記入した後登録し、対象12名全員が試験を完了した。各対象は、以下の通り、配合剤Bの日用量を投与された。
1.1日1回投与によりT(TUとして)を200mg、即ち、2カプセル/投与
2.1日2回投与によりT(TUとして)を200mg(100mg/投与)、即ち、1カプセル/投与
3.1日2回投与によりT(TUとして)を400mg(200mg/投与)
配合剤Bを、性腺機能不全の男性へ1日2回投与した2用量の急性耐容性および定常状態血清薬物動態プロファイルについて試験した。非盲検反復投与クロスオーバー薬物動態試験として、試験を設定した(1つの群で食事の影響を検討した)。
1.1日2回投与でTUとしてのT600mg(300mg/投与)、即ち、3カプセル/投与を7日間連日投与
2.1日2回投与でTUとしてのT400mg(200mg/投与)を8日間連日投与
配合剤Bで、性腺機能不全の男性へ1日2回投与でT(TUとして)200mg(即ち、2カプセル/投与)を28日間処置した場合に、定常状態に達するのに必要となる時間を決定する試験も行った。試験は、非盲検反復投与薬物動態試験として設定した。
性腺機能不全の男性における配合剤Bの薬物動態に対する食事脂肪の任意の影響を、非盲検、2施設、5通りのクロスオーバー試験において試験した。4〜10日の休薬期間の後、T300mgの単回投与(TU475mg、配合剤Bを3カプセル)を、血清ベースラインTレベルが205.5±25.3ng/dL(平均±SE、範囲23〜334.1ng/dL)の性腺機能不全の男性16名に行った。対象を無作為化して、絶食状態で、または具体的量の脂肪(重量%):極低脂肪(6〜10%);低脂肪(20%);「正常な」食事脂肪(30%);または高脂肪(50%)で、約800カロリーを含有する食事摂取の30分後に、薬物を投与した。「正常な」食事は、統計学的比較の目的で比較因子(即ち、参照食)として確立された先験的なものであった。一連の血液試料を、薬物投与の後合計24時間の間に採取し、液体クロマトグラフィー・質量分析法(LC/MS/MS)により血清テストステロンおよびジヒドロテストステロン(DHT)レベルを測定した。
本発明の配合剤の溶解試験をインビトロで行って、インビボで観察されたPKプロファイルとの相関性を評価した。最初の試験では、配合剤Bの溶解を試験した。Andriol Testocaps(登録商標)(ひまし油とラウリン酸プロピレングリコールとの混合物に溶解したソフトゲルあたりTU40mg)を、比較のために含めた。本質的に同じ用量のTU、即ち配合剤B 1カプセル(158.3mg TU)およびTestocapsのソフトゲル4個(40mg×4=160mg TU)を用いて、試験を実施した。溶解(即ち、各配合剤からのTUの放出)を、食事で刺激された腸液を模擬したFed State Simulated Intestinal Fluid(FeSSIF)媒体中で試験した。FeSSIFは、水酸化ナトリウム、氷酢酸、塩化カリウム、レシチン、およびタウロコール酸ナトリウムを含有している。最終的なエマルジョンは、pH5.0に調整されている。
Claims (6)
- 親水性界面活性剤の合計に対する親油性界面活性剤の合計の比(w/w)が6:1〜3.5:1の範囲である、少なくとも1種の親油性界面活性剤および少なくとも1種の親水性界面活性剤を含む担体中に可溶化されたテストステロンウンデカノエートを含み、1日1回または2回の経口投与により300〜1100ng/dLの範囲内に入る定常状態の平均血清テストステロン濃度を提供する経口医薬組成物であって;
親水性界面活性剤は、ポリオキシエチレングリセロールトリヒドロキシステアレートを含み、
親油性界面活性剤は、脂肪酸、および脂肪酸のモノ−グリセリドまたはジ−グリセリドから選択されることを特徴とする、経口医薬組成物。 - 少なくとも1種の親油性界面活性剤が、オレイン酸を含む、請求項1に記載の経口医薬組成物。
- 18〜22重量%の可溶化されたテストステロンウンデカノエートを含む、請求項1に記載の経口医薬組成物。
- テストステロンウンデカノエートが、エタノールを実質的に含まない担体中に可溶化されている、請求項7に記載の経口医薬組成物。
- 12−18重量%の少なくとも1種の親水性界面活性剤を含む、請求項1に記載の経口医薬組成物。
- 50−65重量%の少なくとも1種の親油性界面活性剤を含む、請求項1に記載の経口医薬組成物。
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