JP2013107900A - ガバペンチンプロドラッグ持続放出経口薬剤 - Google Patents
ガバペンチンプロドラッグ持続放出経口薬剤 Download PDFInfo
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- JP2013107900A JP2013107900A JP2013034943A JP2013034943A JP2013107900A JP 2013107900 A JP2013107900 A JP 2013107900A JP 2013034943 A JP2013034943 A JP 2013034943A JP 2013034943 A JP2013034943 A JP 2013034943A JP 2013107900 A JP2013107900 A JP 2013107900A
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- isobutanoyloxyethoxy
- aminomethyl
- carbonyl
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- drug
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Abstract
【解決手段】本発明は、ガバペンチンプロドラッグ、1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤を開示する。当該薬剤は、ガバペンチンが治療に有効である疾患、及び障害を治療する又は予防するために有用である。
【選択図】なし
Description
本願の開示は、ガバペンチンプロドラッグ、1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤、及びかかる薬剤を投与することによる、ガバペンチンが治療に有効である疾患、及び障害を治療する又は予防する方法に関する。
1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸(1)、ガンマアミノ酪酸(GABA)類似体であるガバペンチンのプロドラッグ(2)は、経口的、あるいは哺乳類の結腸に直接的のいずれかで投薬されるとき、ガバペンチンとして高い生体内利用性を有する(Gallop et al., 国際特許公開WO02/100347号;Cundy et al.,J pharmacol Exp Ther.2004,311:315−323;Cundy et al.,J pharmacol Exp Ther.2004,311:324−333)。当該高い生体内利用性は、化合物(1)を、てんかん、痛み(特に神経障害性の痛み、並びに筋肉痛、及び骨格痛)、うつ、不安、精神病、失神発作、運動機能減少、頭蓋障害、神経変性障害、パニック、炎症性障害(すなわち関節症)、不眠症、胃腸障害、ほてり、下肢静止不能症候群、尿失禁、及びエタノール離脱症候群を治療する又は予防するために有用な経口薬剤(持続放出薬剤を含む)の重要な成分とさせる。
本願は、化合物(1)の持続放出経口薬剤を開示する。ある態様において、化合物(1)の持続放出経口薬剤は、約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の絶食した人間の患者に投与するとき、約3μg/mLから約6μg/mLまでの範囲のCmax、約4時間から約7時間までの範囲のTmax、及び約30μg・hr/mLから約70μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する;又は、
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の食物を与えられた人間の患者に投与するとき、約5μg/mLから約8μg/mLまでの範囲のCmax、約6時間から約11時間までの範囲のTmax、及び約60μg・hr/mLから約110μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する。
(b)約1重量%〜約50重量%の放出速度改良ポリマーを含むタブレットとなり得、ここで重量%は当該製剤の総乾燥重量に基づく。好適な放出速度改良ポリマーは、グリセリルモノステアレート、グリセリルベヘネート、グリセリルパルミトステアレート、ラウロイルマクロゴールグリセリド、及びステアロイルマクロゴールグリセリドの如きグリセリルエステルを含む。他の好適な放出速度改良ポリマーはメタクリレート共重合体、アンモニオアルキルメタクリレート共重合体、並びにそれらの共重合体、及び組み合わせを含む。
「AUC」は、患者への当該化合物の投与後の時間の関数として、患者における体液中の当該化合物又はそれらの代謝体の濃度を示す曲線下の面積である。ある態様において、当該化合物はプロドラッグとなり得、及び代謝体は薬物となり得る。体液の例は、血液、及び血しょうを含む。AUCは、様々な時間間隔で、液体クロマトグラフィータンデム質量分析(LC/MS/MS)の如き方法を使用して、血しょう又は血液の如き体液中の化合物又はそれらの代謝体の濃度を測定し、及び血しょうの濃度対時間曲線下の面積を計算することにより、決定され得る。薬物の濃度対時間曲線からAUCを計算するための好適な方法は、本分野においてよく知られているだろう。本願明細書の開示に関して、ガバペンチンについてのAUCは、化合物(1)、1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む薬剤の経口投与後の患者の血しょう、及び/又は血液中のガバペンチンの濃度を測定することにより決定され得る。
本明細書に開示されるある態様は、タブレット形状における持続放出経口薬剤を提供するけれども、持続放出経口薬剤の分野における当業者は、粉末、粒子、サシェ、液体懸濁液、及び/又は再構成のためのカプセルの如き他の持続放出経口薬剤も使用され得ることを理解するだろう。ある態様において、薬剤はタブレットとなり得、それは、回転楕円形、角ばった楕円形又は長円体の如き薬剤の経口投与に適したいずれかの形状の内の1つとなり得る。1つのタブレットは、化合物(1)の1単位用量を含み得、又は1単位用量未満を含むミニタブレットの場合、ミニタブレットは、1単位用量を提供するためにカプセルに入れ込まれ得る。
本発明の持続放出経口薬剤は、親薬物であるガバペンチンが治療に有効だと知られている又は今後そのことが発見されるいずれかの疾患又は障害に苦しむ患者に投与され得る。ガバペンチンが処方される症状、及びそれ故本発明の薬剤もまた有効である症状は、てんかん、うつ、不安、精神病、認知、統合失調症、失神発作、運動機能減少、頭蓋障害、神経変性障害、パニック、痛み{特に、神経障害性の痛み(例えばヘルペス後神経痛)、筋肉痛、及び骨格痛}、下肢静止不能症候群、ほてり、尿失禁、炎症性障害(すなわち関節症)、不眠症、胃腸障害、アルコール/コカイン中毒、エタノール離脱症候群、外陰病変、早漏、及びグルタミン酸作動性のようなものを含む。
本明細書中に記載される特定の疾患、障害又症状の治療において有効であろう化合物(1)の量は、当該疾患又は症状の性質に、少なくとも部分的に、依存するだろうし、前術のような本分野において知られる標準的臨床技術により決定され得る。さらに、生体外又は生体内アッセイが場合により使用され、最適な用量範囲の特定を補助する。投与されるプロドラッグの量は、もちろん、他の要因間で、治療される疾患を患う対象、当該対象の重さ、当該苦痛の重篤度、投与様式、及び処方する医師の判断に依存するだろう。
化合物(1)を含む持続放出経口薬剤タブレットを表1に示される成分を有するように製造した。
表1に示される成分を有する持続放出経口製剤タブレットを、以下のステップに従う異なる方法を使用して製造した。化合物(1)、第2リン酸カルシウム、グリセリルベヘネート、滑石、及びコロイド状シリコンジオキシドの重さを量り、#20メッシュスクリーンを通してスクリーニングし、そしてV−ブレンダー中で15分間混合した。ラウリル硫酸ナトリウムの圧縮分の重さを量り、そして#30メッシュスクリーンを通した。ステアリン酸マグネシウムの圧縮分の重さを量り、そして#40メッシュスクリーンを通した。スクリーニングされたラウリル硫酸ナトリウム、及びステアリン酸マグネシウムを、V−ブレンダーに添加し、そして5分間混合した。当該混合物を排出し、そして、Chilsonator機(FitzPatrick、Elmhurst,ILによるローラー圧縮機)上でコンパクトに圧縮した。次いで、得られたコンパクトを、ハンマーミル(FitzPatrick,Elmhurst,NJ)に通し、さらなる圧縮のための製粉された材料を得た。ラウリル酸硫酸ナトリウムのタブレット分の重さを量り、そして#30メッシュスクリーンを通した。ステアリン酸マグネシウムのタブレット分の重さを量り、そして#40メッシュスクリーンを通した。当該製粉された材料、及び当該ラウリル硫酸ナトリウム、及びステアリン酸マグネシウムのタブレット分をV−ブレンダーに添加し、そして3分間混合した。当該混合された材料を排出し、そして、圧縮し、1310mgの総重量、及び600mg(45.8重量%)の化合物(1)積載量を有するタブレットを形成した。当該タブレットを、300mgの化合物(1)積載量を有する655mgのタブレットにも圧縮した。当該タブレットは、各々、15.7〜18.9kp、そして11.1〜13.7kpの平均最終硬度を有した。
成人健常者における化合物(1)の持続放出経口薬剤の、安全性、耐容性、及び薬物動態についての、無作為化交差、絶食した/食物を与えられた単回投与試験を実施した。実施例1の持続放出経口薬剤を使用した。当該試験を、商業的なガバペンチンカプセル製剤(Neurontin)(登録商標)と比較して人間におけるこの薬剤の能力を評価するように計画した。12人の成人健常者(7人の男性、及び5人の女性)がこの試験に参加した。平均体重は、75.6kgだった。全患者は、治療と治療との間に1週間のウォッシュアウトを有し、無秩序な順番に異なる治療を受けた。当該2つの治療とは、(A)一晩食物を与えられた後の実施例1のタブレットの単回投与{2×600mg化合物(1)};及び(B)高脂肪朝食の後に実施例1の単回投与{2×600mg化合物(1)}であった。
食物を与えられた人間の患者に対する、実施例2に従って製造された持続放出経口薬剤の経口投与後、ガバペンチンの平均血しょう濃度を、図3に示す。12人の人間の患者におけるガバペンチンの平均血しょう濃度を、(a)300mgの化合物(1)を含む1つのタブレット、(b)600mgの化合物(1)を含む1つのタブレット、及び(c)各タブレットが600mgの化合物(1)を含む2つのタブレット中の1200mgの化合物(1)の投与後、実施例3に記載される方法に従って測定した。
カニクイザルに対する、実施例1に従って製造された持続放出経口薬剤の経口投与後のガバペンチンの血中濃度±1SDを、図4に示す。カニクイザルにおけるガバペンチンの血中濃度を、以下の手順に従い測定した。
化合物(1)を含むタブレット{タブレットあたり1×600mg化合物(1)}を、4匹の成人で雄のカニクイザル(Macaca fascicularis)(約3kgの体重)の一群に経口投薬により投与した。各サルに1つのタブレットを投与した。動物に、試験前の一晩、及び投薬後約4時間、絶食させた。血液サンプル(1.0mL)を、経口投薬後、24時間に渡り、大腿静脈経由で得た。
300μLのメタノールを、サンプル及びスタンダードの製造のために、1.5mLのエッペンドルフチューブに添加した。
当該サルの血液中のガバペンチンの濃度を、Shimadzu SLC−10AVP、及びLEAPオートサンプラーを装備したAPI2000LC/MS/MS器具を使用して測定した。カラムは、室温で動作するZorbax C8XDB4.6×150mmカラムだった。移動相は、(A)水中に0.1%ギ酸、及び(B)アセトニトリル中に0.1%ギ酸だった。勾配条件は、3.5分間の2%B、3.5分間で95%Bに増大し2分間維持、次いで5.6分間で2%Bまで低減、そして2.3分間維持だった。30μLのサンプルを当該カラム中に注入した。Turbo−IonSpray源を使用し、そしてガバペンチンを、172/137のMRMトランジションについて陽イオンモードにおいて検出した。ピークを、Analyst1.2定量ソフトウェアを使用して調整した。
実施例6に従って製造された持続放出経口薬剤の、カニクイザルに対する経口投薬後(1×600mg)のガバペンチンの血中濃度±1SDを、図5に示す。カニクイザルにおけるガバペンチンの血中濃度を、実施例5に記載された方法に従い測定した。
以下のステップを使用し、実施例1、2、及び6に従って製造された薬剤の生体外溶解プロフィールを測定した。薬剤を、37℃で、10mMリン酸2水素カリウム緩衝液(KH2PO4、pH7.4)及び1%(wt/体積)ラウリル硫酸ナトリウムの900mLを含む溶解容器中に配置した。当該溶解媒体を50rpm(USP,タイプII、パドル)で撹拌した。サンプルを0.5、1、2、4、6、8、12、及び24時間で回収し、溶液中の化合物(1)の含有量を、210nmでのフォトダイオード検出を有する、C18カラム、及びリン酸緩衝液/アセトニトリル/水の等張移動相を使用する逆相HPLCにより測定した。
Claims (35)
- 1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤であって、以下:
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の絶食した人間の患者に投与するとき、約3μg/mLから約6μg/mLまでの範囲のCmax、約4時間から約7時間までの範囲のTmax、及び約30μg・hr/mLから約70μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する;又は、
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の食物を与えられた人間の患者に投与するとき、約5μg/mLから約8μg/mLまでの範囲のCmax、約6時間から約11時間までの範囲のTmax、及び約60μg・hr/mLから約110μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する、
前記持続放出経口薬剤。 - 1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤であって、以下:
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の絶食した人間の患者に投与するとき、図1に示されるプロフィールと生物学的に同等なガバペンチン血しょう濃度プロフィールを提供する;又は、
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、1又は複数の食物を与えられた人間の患者に投与するとき、図2に示されるプロフィールと生物学的に同等なガバペンチン血しょう濃度プロフィールを提供する、
前記持続放出経口薬剤。 - 以下の:
(a)約10重量%〜約80重量%の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸;及び
(b)約1重量%〜約50重量%の放出速度改良ポリマー、
を含み、ここで重量%は当該製剤の総乾燥重量に基づく、請求項1、又は2のいずれか1項に記載の薬剤。 - 前記薬剤がタブレットを含む、請求項3に記載の薬剤。
- 前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸が約30重量%〜約75重量%であり、前記放出速度改良ポリマーが約1重量%〜約50重量%である、請求項3に記載の薬剤。
- 前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸が約40重量%〜約65重量%であり、前記放出速度改良ポリマーが約1重量%〜約50重量%である、請求項3に記載の薬剤。
- 前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸が約50重量%〜約60重量%であり、前記放出速度改良ポリマーが約20重量%〜約50重量%である、請求項3に記載の薬剤。
- 前記放出速度改良ポリマーが、脂肪族化合物、及びメタクリル酸共重合体から選択される、請求項3に記載の薬剤。
- 前記脂肪族化合物が、グリセリルエステルである、請求項8に記載の薬剤。
- 前記グリセリルエステルが、グリセリルモノステアレート、グリセリルベヘネート、グリセリルパルミトステアレート、ラウロイルマクロゴールグリセリド、ステアロイルマクロゴールグリセリド、及び前述のいずれかの組み合わせから選択される、請求項9に記載の薬剤。
- 前記グリセリルエステルが、グリセリルベヘネートである、請求項10に記載の薬剤。
- 前記脂肪族化合物が、ラウリルアルコール、ミリスチルアルコール、ステアリルアルコール、セチルアルコール、セトステアリルアルコール、ステアリン酸、パラフィンワックス、蜜ろう、グリコワックス、キャスターワックス、カルナバワックス、及び前述のいずれかの組み合わせから選択される請求項8に記載の薬剤。
- 前記メタクリル酸共重合体が、アクリル酸エステル共重合体、メタクリル酸エステル共重合体、及び前述のいずれかの組み合わせから選択される、請求項8に記載の薬剤。
- 約50mg〜約800mgの範囲の量の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項3に記載の薬剤。
- 約100mg〜約800mgの範囲の量の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項3に記載の薬剤。
- 約300mg〜約700mgの範囲の量の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項3に記載の薬剤。
- 前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸が、結晶性形状である、請求項3に記載の薬剤。
- 希釈剤、滑剤、抗粘着剤、流動促進剤、界面活性剤、崩壊剤、及び前述のいずれかの組み合わせから選択される、1又は複数の医薬として許容される賦形剤をさらに含む、請求項3に記載の薬剤。
- 前記希釈剤が、第2リン酸カルシウム、及び微晶性セルロ−スから選択される、請求項18に記載の薬剤。
- 前記薬剤が、約600mgの1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含むタブレットであり、かつ、その投与量が、2つの前記タブレット及び約1200mgの1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項1又は2のいずれか1項に記載の薬剤。
- コーティングを含む、請求項3に記載の薬剤。
- 約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記1又は複数の絶食した人間の患者に投与するとき、約3μg/mLから約6μg/mLまでの範囲のCmax、約4時間から約7時間までの範囲のTmax、及び約30μg・hr/mLから約70μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する;及び
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記1又は複数の食物を与えられた人間の患者に投与するとき、約5μg/mLから約8μg/mLまでの範囲のCmax、約6時間から約11時間までの範囲のTmax、及び約60μg・hr/mLから約110μg・hr/mLまでの範囲のAUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する、
請求項1に記載の薬剤。 - 約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記絶食した人間の患者群に投与するとき、約3μg/mLから約6μg/mLまでの範囲の平均Cmax、約4時間から約7時間までの範囲の平均Tmax、及び約30μg・hr/mLから約70μg・hr/mLまでの範囲の平均AUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する;及び、
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記食物を与えられた人間の患者群に投与するとき、約5μg/mLから約8μg/mLまでの範囲の平均Cmax、約6時間から約11時間までの範囲の平均Tmax、及び約60μg・hr/mLから約110μg・hr/mLまでの範囲の平均AUCにより特徴付けられるガバペンチン血しょう濃度プロフィールを提供する、
請求項1に記載の薬剤。 - 約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記1又は複数の絶食した人間の患者に投与するとき、図1に示されるプロフィールと生物学的に同等なガバペンチン血しょう濃度プロフィールを提供する;及び
約1100mgから約1300mgまでの範囲の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の用量で、前記1又は複数の食物を与えられた人間の患者に投与するとき、図2に示されるプロフィールと生物学的に同等なガバペンチン血しょう濃度プロフィールを提供する、
請求項2に記載の薬剤。 - 前記1又は複数の絶食した人間の患者は、前記薬剤を投与する前の約10時間から投薬後約4時間までいかなる食物をも食べず、投薬前約2時間と約1時間に約250mLの水を飲み、及び投薬後約2時間に約250mLの水を飲み、投薬後約4時間に昼食を食べ、そして投薬後約10時間に夕食を食べる;並びに、
前記1又は複数の食物を与えられた人間の患者は、前記薬剤を投与する前の約30分前に試験食を食べ始め、当該薬剤を投与する前の約5分前に当該試験食を食べ終え、投薬後約4時間に昼食を食べ、そして投薬後約10時間後に夕食を食べる、ここで当該試験食は、その中で約500カロリーが脂肪のカロリーを構成する約1000総カロリーを含む、
請求項1又は2のいずれか1項に記載の薬剤。 - かかる治療を必要とする患者に、請求項1又は2のいずれか1項に記載の薬剤を投与することを含む、神経障害性の痛み、てんかん、下肢静止不能症候群、ほてり、尿失禁、早漏、及び外陰病変から選択される疾患又は症状を治療する方法。
- 前記痛みが、ヘルペス後神経痛を含む、請求項26に記載の方法。
- 10mMのリン酸2水素カリウム緩衝液、及びpH7.4で1%(重量/体積)のラウリル硫酸ナトリウムの中に置かれ、そして37℃、50rpm(USP、タイプII)で撹拌されたとき、約2時間後に前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の約20%、約5時間後に約50%、及び約8時間後に約80%を放出する、1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤。
- 以下の:
(a)約10重量%〜約80重量%の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸;及び
(b)約1重量%〜約50重量%の放出速度改良ポリマー、
を含み、ここで重量%は当該製剤の総乾燥重量に基づく、請求項28に記載の薬剤。 - 約500mg〜約700mgの範囲の量の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項29に記載の薬剤。
- 第2リン酸カルシウムをさらに含む、請求項29に記載の薬剤。
- 10mMのリン酸2水素カリウム緩衝液、及びpH7.4で1%(重量/体積)のラウリル硫酸ナトリウムの中に置かれ、そして37℃、50rpm(USP、タイプII)で撹拌されたとき、約5時間後に前記1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の約30%、約10時間後に約60%、及び約15時間後に約80%を放出する、1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸の持続放出経口薬剤。
- 以下の:
(a)約10重量%〜約80重量%の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸;及び
(b)約1重量%〜約50重量%の放出速度改良ポリマー、
を含み、ここで重量%は当該製剤の総乾燥重量に基づく、請求項32に記載の薬剤。 - 約500mg〜約700mgの範囲の量の1−{[(α−イソブタノイルオキシエトキシ)カルボニル]アミノメチル}−1−シクロヘキサン酢酸を含む、請求項33に記載の薬剤。
- 微晶性セルロースをさらに含む、請求項33に記載の薬剤。
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