JP2021508713A - ドネペジルを含有する認知症治療用経皮吸収製剤 - Google Patents
ドネペジルを含有する認知症治療用経皮吸収製剤 Download PDFInfo
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- JP2021508713A JP2021508713A JP2020536165A JP2020536165A JP2021508713A JP 2021508713 A JP2021508713 A JP 2021508713A JP 2020536165 A JP2020536165 A JP 2020536165A JP 2020536165 A JP2020536165 A JP 2020536165A JP 2021508713 A JP2021508713 A JP 2021508713A
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- donepezil
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- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- AIMUHNZKNFEZSN-UHFFFAOYSA-M sodium;decane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCS([O-])(=O)=O AIMUHNZKNFEZSN-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229920002725 thermoplastic elastomer Polymers 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
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Abstract
【選択図】図1
Description
薬物含有層は、(a)有効成分としてドネペジル又はその薬学的に許容される塩、(b)可溶化剤としてモノカプリル酸プロピレングリコール、(c)粘着基剤としてスチレン−イソプレン−スチレンブロック共重合体(SIS)を含有する、認知症治療用経皮吸収製剤を提供する。
様々な可溶化剤に対してドネペジルの溶解度評価を行った。
カラム:Capcellpak C18、4.6×150mm、5μm
移動相:デカンスルホン酸ナトリウム(Sodium decanesulfonate)2.5gを水650mLに完全に溶解させた後、70%過塩素酸1mL及びアセトニトリル溶液350mLを添加した。得られた溶液を濾過した後、超音波洗浄機で気泡を除去して移動相として使用した。
流速:1.4mL/min
サンプル注入量:20μL
紫外部吸光光度計:271nm
図1から分かるように、溶解度評価の結果、オレイン酸が最も高いドネペジル溶解度を示し、溶解度の結果に基づいて、ドネペジル溶解度が高い9種の可溶化剤を用いて下記の実施例及び比較例のドネペジル含有経皮吸収製剤を製造した。
下記表1に記載された組成でスチレン−イソプレン−スチレンブロック共重合体5.2g、ミリスチン酸オクチルドデシル8.2g及びモノカプリル酸プロピレングリコール4.5gを酢酸エチル15gに溶かした後、ドネペジル1gを加えて均質に溶かした。得られた溶液をシリコンコーティングされたPETフィルムに塗布して80℃のオーブンで30分間乾燥させた後、バッキングフィルム(Backing film)とラミネートして経皮吸収製剤を製造した。
粘着付与樹脂であるテルペン樹脂の添加有無による皮膚透過度、結晶析出を確認するために、下記表1に記載された組成にして、前記実施例1と同様の方法でドネペジル含有経皮吸収製剤を製造した。
下記表2に記載された組成で本発明の実施例1と同様の組成成分の量を異にした実施例3、及び実施例1とは可塑剤成分を異にした実施例4を実施例1と同様にして、ドネペジル含有経皮吸収製剤を製造した。
本発明のドネペジルとモノカプリル酸プロピレングリコールの最適な比率を選定するために、実施例2とは可溶化剤の量を異にした実施例5−1乃至5−3を実施例2と同様の方法で下記表3に記載された組成にして、経皮吸収製剤を製造した。
本発明の粘着基剤としてスチレン−イソプレン−スチレンブロック共重合体の最適な比率を選定するために、実施例2とは粘着剤の量を異にした実施例6−1乃至6−6を実施例2と同様の方法で下記表4に記載された組成にして、経皮吸収製剤を製造した。
前記実験例1の結果から示された溶解度結果に基づいて選定されたドネペジル溶解度が高い8種の可溶化剤を含み、前記実施例2とは可溶化剤のみを異にした下記表5に記載された組成で実施例2と同様の方法で経皮吸収製剤を製造してそれぞれ比較例1乃至8とし、可溶化剤を含まない経皮吸収製剤を比較例9とした。
本発明の実施例1とは粘着基剤を異にした比較例10乃至12を実施例1と同様の方法で下記表6に記載された組成にして、経皮吸収製剤を製造した。比較例10乃至12の粘着剤として、それぞれEVA系粘着剤であるポリエチレン酢酸ビニル(酢酸ビニル含有量40%)、アクリル系粘着剤であるDuro−Tak(登録商標)87−9301及びポリイソブチルレン系粘着剤を使用した。ポリイソブチレンを使用した場合、有機溶媒としてヘキサンを使用した。
本発明のドネペジルとモノカプリル酸プロピレングリコールの最適な比率を選定するために、実施例2とは可溶化剤の量を異にした比較例13を実施例2と同様の方法で下記表7に記載された組成にして、経皮吸収製剤を製造した。
実施例1〜6及び比較例1〜13で製造されたそれぞれの経皮吸収製剤のin−vitro透過度評価を、薬物透過実験用拡散装置(Franz−cell)を用いて行った。レセプターチャンバーに、レセプター溶液として10%エタノール及び0.02%アジ化ナトリウム(sodium azide)が添加された生理食塩水を入れ、温度を32±0.5℃に維持した。皮膚は、ヘアレスラット皮膚(Hairless Rat Skin)を用いて実施例1〜6及び比較例1〜13で製造されたそれぞれの経皮吸収製剤を供与セルのサイズに合わせてカットして適用させた。時間経過に伴うドネペジル透過量を液体クロマトグラフィー法で測定した。実施例1〜6及び比較例1〜13で製造されたパッチの時間による薬物放出様相を図2乃至図6に示した。
図2に示すように、可溶化剤が添加されていない比較例9の場合、ドネペジルが殆ど透過しなかった。また、ドネペジルに対する溶解度が高かったオレイン酸(比較例8)も、非常に低い透過度を示すのに対し、可溶化剤としてモノカプリル酸プロピレングリコールを添加した実施例1は、皮膚透過度が著しく増加することが分かった。これにより、モノカプリル酸プロピレングリコールの優れた皮膚透過度を確認することができた。
図3に示すように、テルペン樹脂が添加された実施例1とテルペン樹脂が添加されていない実施例2の皮膚透過度は、変わりがなかった。
図4に示すように、可塑剤としてミリスチン酸オクチルドデシルをミネラルオイルに変更させた実施例3及び4の皮膚透過度は、変化がなかった。これに対し、粘着基剤を変更した比較例10〜12の場合は、粘着基剤としてスチレン−イソプレン−スチレンブロック共重合体を用いた場合に比べて、皮膚透過度が著しく低下することが分かった。
実施例5と比較例13によって製造された経皮吸収製剤を実験用拡散装置を用いて評価した。その結果、ドネペジル:モノカプリル酸プロピレングリコールの比率が1:0.75以下(比較例13)の場合には、薬物結晶が析出して皮膚透過度が著しく低下した。ドネペジル:モノカプリル酸プロピレングリコールの比率が1:1.5〜1:4.5である場合には、薬物結晶析出なしに皮膚透過度が高かった。
薬物含有層内のスチレン−イソプレン−スチレンブロック共重合体の最適な比率を確認するために、実施例6によって製造された経皮吸収製剤を実験用拡散装置を用いて評価した。
実施例1〜6で製造された経皮吸収製剤の薬物結晶析出有無を評価した。結晶析出様相は、実施例1〜6によって製造された経皮吸収製剤を25℃、60%RHで1ヶ月間保管した後、結晶の生成を顕微鏡で観察した。その結果は、下記表8のとおりである。
本発明に係るドネペジル経皮吸収製剤の皮膚刺激性の程度を評価した。上記の評価のために、本発明の実施例6−5で製造された経皮吸収製剤と、比較例として市販品のエクセロン5mgのパッチを使用した。
本発明の実施例1、実施例6−5で製造された経皮吸収製剤の薬物動態評価をヘアレスラット(Hairless rat)を用いて評価して表11に示した。比較のために、比較例の中でin−vitro皮膚透過度評価の結果、皮膚透過度に最も優れた比較例3(可溶化剤としてトリアセチンを用いた経皮吸収製剤)及び経口投与剤としての参考例1(ドネペジル5mg含有の経口用組成物)を一緒に評価した。
実施例1と比較例3は、可溶化剤を除いては同じ組成を有する経皮吸収製剤であって、2.5cm2の大きさに成形し、実施例6−5は、経皮吸収製剤をそれぞれ4cm2、8cm2の大きさに成形してヘアレスラットに貼り付けた後、7日後にパッチを脱着した。パッチ貼付後0、4、8、24、30、48、72、96、144、168時間に採血して血漿中のドネペジル量を測定した。参考例1は、蒸留水にドネペジルを2.5mg/mlで溶解させた後、ドネペジル溶液2mlを経口投与した。投与後0、0.5、1、2、4、6、24時間に採血して血漿中のドネペジル量を測定した。
Claims (9)
- 支持層、薬物含有層及び剥離層で構成された経皮吸収製剤において、
薬物含有層は、(a)有効成分としてドネペジル又はその薬学的に許容される塩、(b)可溶化剤としてモノカプリル酸プロピレングリコール、及び(c)粘着基剤としてスチレン−イソプレン−スチレンブロック共重合体を含有する、認知症治療用経皮吸収製剤。 - 前記ドネペジルが遊離塩基(free base)形態であることを特徴とする、請求項1に記載の認知症治療用経皮吸収製剤。
- モノカプリル酸プロピレングリコールが全体薬物含有層の1〜40重量%であることを特徴とする、請求項1に記載の認知症治療用経皮吸収製剤。
- モノカプリル酸プロピレングリコールが全体薬物含有層の3〜30重量%であることを特徴とする、請求項3に記載の認知症治療用経皮吸収製剤。
- モノカプリル酸プロピレングリコールが全体薬物含有層の5〜25重量%であることを特徴とする、請求項4に記載の認知症治療用経皮吸収製剤。
- スチレン−イソプレン−スチレンブロック共重合体が全体薬物含有層の10〜70重量%であることを特徴とする、請求項1に記載の認知症治療用経皮吸収製剤。
- 前記薬物含有層には可塑剤をさらに含むことを特徴とする、請求項1に記載の認知症治療用経皮吸収製剤。
- 前記可塑剤が、パラフィン系プロセスオイル、ナフテン系プロセスオイル、芳香族系プロセスオイル、オリーブ油、ツバキ油、トールオイル、ヒマシ油、ミリスチン酸イソプロピル、ラウリン酸ヘキシル、ミネラルオイル、ミリスチン酸オクチルドデシル、及びプロピレングリコールよりなる群から選ばれた一つ以上のものであることを特徴とする、請求項7に記載の認知症治療用経皮吸収製剤。
- (a)有機溶媒にモノカプリル酸プロピレングリコール、スチレン−イソプレン−スチレンブロック共重合体、及びドネペジル遊離塩基を溶解させるステップと、(b)前記(a)ステップで製造された溶液を剥離層に塗布し、乾燥させて薬物含有層を形成するステップと、(c)前記薬物含有層を支持層とラミネートするステップとを含む、経皮吸収製剤の製造方法。
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