JP7382957B2 - アピキサバン製剤 - Google Patents
アピキサバン製剤 Download PDFInfo
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- JP7382957B2 JP7382957B2 JP2020556976A JP2020556976A JP7382957B2 JP 7382957 B2 JP7382957 B2 JP 7382957B2 JP 2020556976 A JP2020556976 A JP 2020556976A JP 2020556976 A JP2020556976 A JP 2020556976A JP 7382957 B2 JP7382957 B2 JP 7382957B2
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- apixaban
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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Description
本出願は、参照により全体が本明細書に取り込まれる2018年4月16日提出の仮出願番号第62/658,175号の利益を主張するものである。
本発明は、アピキサバン医薬製剤に関する。
アピキサバン固形製剤(例えば、錠剤またはカプセル剤)を、嚥下が困難な患者に経口投与することが課題となっている。経口投与を容易にするために、例えば、食物または飲料中への分散および/または溶解に適するアピキサバン固形製剤を開発するために検討が行われた。
Z’は、非対称単位あたりの分子数である。
T(℃)は、結晶学的データのための温度である。
Vm=V(単位格子)/(ZZ’)
本発明による典型的な製剤を表5に供する。
実施例1に記載されるアピキサバンスプリンクルカプセル製剤の相対的バイオアベイラビリティを一連の試験により評価した。
嗜好性評価結果の概要を表7に示す。
アピキサバンのSLDコーティングは、Wursterの底面スプレー構造(bottom-spray configuration)流動床コーターを用いて行った。前記製剤は、Sugletコア基質および10%のコーティング重量(1/99のアピキサバン/担体)の活性成分コーティングから構成された。
アピキサバンのSLDコーティングは、Wursterの底面スプレー構造(bottom-spray configuration)流動床コーターを用いて行った。前記製剤は、Sugletコア基質および10%のコーティング重量(1/99のアピキサバン/担体)の活性成分コーティングから構成された。
アピキサバンのSLDコーディングは、Wursterの底面スプレー構造(bottom-spray configuration)流動床コーターを用いて行った。前記製剤は、Sugletコア基質および10%のコーティング重量(1/99のアピキサバン/担体)の活性成分コーティングから構成された。
安定性を試験するために、実施例4に従って調製したカプセル剤を、HIS中の25℃/60%RHおよび40℃/75%RHでHDPEボトル内に密封し保存し、外観、SEMによる形態、溶出、アッセイ/関連する物質、および水含有量について、2週間、1ヶ月、および2ヶ月後に試験した。最初のデータと比較して、いずれの条件におけるこれらの測定のいずれにおいても目立った変化は観察されなかった。これらのデータに基づいて、カプセル化された処置されたコアは、両条件でおいて少なくとも2ヶ月間化学的かつ物理的に安定であると考えられる。
Claims (18)
- コア基質、ならびに前記コア基質上のアピキサバンおよび担体を含む、処置されたコアであって、0.001w/w%~0.20w/w%のアピキサバンを含み、
前記アピキサバンおよび担体が、前記コア基質の表面上に形成された層中に存在し、ならびに
前記アピキサバンおよび担体が、溶解度上限以下の溶媒中のアピキサバン濃度で行われるスプレー層状分散により前記コア基質の表面に塗布される、処置されたコア。 - 前記コア基質が、糖ビーズもしくは球体、または微結晶セルロース、乳糖もしくはマンニトール粒子である、請求項1に記載の処置されたコア。
- 150ミクロン~355ミクロンのサイズを有する、請求項1または2に記載の処置されたコア。
- 請求項1~3のいずれか1項に記載の、少なくとも1つの処置されたコアを含む、製剤。
- (a)0.09w/w%~0.11w/w%のアピキサバン含有量を有し、
(b)9w/w%~11w/w%の担体含有量を有し、
(c)89w/w%~91w/w%のコア基質含有量し、または
(d)0.1w/w%のアピキサバン含有量を有する、請求項4に記載の製剤。 - 少なくとも1つの前記処置されたコアが、カプセル中に存在する、請求項4または5に記載の製剤。
- 前記カプセルが、ゼラチンカプセル、HPMCカプセル、またはスプリンクルカプセルである、請求項4~6のいずれか1項に記載の製剤。
- 前記カプセルが、0.1mgのアピキサバンを含むものである、請求項6または7に記載の製剤。
- 請求項1~3のいずれか1項に記載の少なくとも1つの処置されたコアを含むことを特徴とする、治療を必要とする対象における血栓塞栓性障害の治療剤であって、前記治療が、少なくとも1つの処置されたコアを、液体担体中に分散させ、および/または溶解させ、次いで前記液体担体を前記対象に投与することを含む、治療剤。
- 前記液体担体が、食物または飲料である、請求項9に記載の治療剤。
- 前記対象が、新生児である、請求項9または10に記載の治療剤。
- 血栓塞栓性障害の治療における使用または血栓塞栓性障害の治療剤の製造における使用のための、請求項4~8のいずれか1項に記載の製剤。
- 0.1mg~0.4mgのアピキサバンを含む、請求項4または5に記載の製剤。
- 0.2mgのアピキサバンを含む、請求項13に記載の製剤。
- 0.3mgのアピキサバンを含む、請求項13に記載の製剤。
- 0.4mgのアピキサバンを含む、請求項13に記載の製剤。
- 前記少なくとも1つの処置されたコアが、カプセル中に存在する、請求項13~16のいずれか1項に記載の製剤。
- 前記カプセルが、スプリンクルカプセルである、請求項17に記載の製剤。
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