JP6446035B2 - 経皮的デリバリーシステム - Google Patents
経皮的デリバリーシステム Download PDFInfo
- Publication number
- JP6446035B2 JP6446035B2 JP2016514478A JP2016514478A JP6446035B2 JP 6446035 B2 JP6446035 B2 JP 6446035B2 JP 2016514478 A JP2016514478 A JP 2016514478A JP 2016514478 A JP2016514478 A JP 2016514478A JP 6446035 B2 JP6446035 B2 JP 6446035B2
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- Prior art keywords
- nitrite
- hydrogel
- dressing system
- layer
- mesh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 62
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Description
本発明は薬学的に有効な薬品の経皮的なデリバリー用システムに関する。
皮膚を通した物質の浸透は毒物学上・治療上の観点から重要である。上皮を横切ったほとんどの化合物の受動的デリバリーは、これらの上皮によって与えられた優れた障壁特性により制限される。角皮層はほとんどの化学薬品の浸透への本質的な障害である。
本発明の発明者は、薬学的に有効な薬品の経皮的なデリバリーに役立つ、改善されたシステムを開発した。システムは、NOの生産のために亜硝酸塩に対する酸性化の効果を提供するためにヒドロゲルを利用する。皮膚に接してそれを直接置くことができ、傷から浸出物を吸収することができるので、ヒドロゲルの使用は有利である。
(i) 亜硝酸塩を含んでいる層;および
(ii)水素イオンを含んでいるヒドロゲル;
ここで、亜硝酸塩を含む層および/またはヒドロゲルは、薬学的に有効な薬品を含む。
本発明のシステムは、亜硝酸塩を含んでいる層を含む第1の成分、および水素(H+)イオンを含んでいるヒドロゲルを含む第2の成分を含む、2つの構成要素のシステムである。第1の成分あるいは第2の成分のいずれかは、さらに薬学的に有効な薬品を含む。
2つの成分が互いに接して置かれる場合、化学反応が起こって一酸化窒素(NO)を生産する。2つの成分は以下に詳細に記述される。
層は固体または溶液形態の亜硝酸塩を含んでいる。典型的には、亜硝酸塩は、亜硝酸塩溶液の形をしている。層は、たとえば亜硝酸塩の溶液に層をつけることにより、典型的には亜硝酸塩を吸収させるか、あるいは含浸させる。亜硝酸塩は、典型的に亜硝酸塩イオンの薬理学的に受理可能な源あるいはそのような亜硝酸塩の前駆物質である。
しかしながら、pHバッファーの追加は典型的に必要ではない。
この例は、以下を含むドレッシングシステムの生産について記述する:
(i) 亜硝酸塩を含んでいる層;および
(ii)水素イオンを含んでいるヒドロゲル。
第一層:傷接触メッシュ(1M亜硝酸ナトリウムを含む)
メッシュは、 Sodium Nitrite Extra Pure ph Eur, USP メルク社製からの、1M亜硝酸ナトリウムと脱イオン水の溶液に浸漬されたポリプロピレン・メッシュ(RKWグループ製)である。
亜硝酸ナトリウムは適切なサイズのベッセルへ計量投入され、次に、計量された体積の脱イオン水へ注意深く移される。その後、完全に溶解するまで撹拌され、適切な濃度の溶液を調製した。この実施態様では、亜硝酸ナトリウム溶液はメッシュ上に分配され、次に亜硝酸ナトリウム溶液をメッシュに吸収するための最小時間で、各ペトリ皿に入れられる。完成品は照射によって殺菌される。
この研究用に選ばれたヒドロゲルは、吸収に対する高い能力を持っており、湿った創傷治癒環境を促進する。ヒドロゲルは、架橋された陰イオン性共重合体、およそ30%の水、およびおよそ30%のグリセリンを含む。この層は、ドレッシングにバクテリアへの障壁および美学的に好ましい外側表面を提供するために一体化されたポリウレタンフイルムを有する。ゲルはいくつかのカルボン酸基の存在から生ずる約4.2−4.6の表面pHを有する。これらの基は一酸化窒素への亜硝酸ナトリウムからの変換のために酸性度を提供する。カルボン酸基がヒドロゲル・ネットワークに共有結合で結合されるので、それらは傷へリリースされない。
ヒドロゲルは以下に述べられた成分のリストから製造される。製造のプロセスは特許EP1100555B1およびEP110556B1でのものである。それは参照されそれらの全体が本明細書に組み入れられる。
完成品はガンマ線照射によって殺菌される。
モノマー、ナトリウムAMPS 2405A(水中の58%の溶液)(Lubrizol)
モノマー、アクリル酸(BASF)
グリセリンBP、EP(H. Fosters)
Darocur 1173、2−ヒドロキシ−2−メチルプロピオフェノン(BASF)
SR 344、ポリ(エチレングリコール)ジアクリレート(Sartomer)
メッシュ、漉かれた不織布の20gsm(RKWグループ)
Inspire 2304、ポリウレタンフイルム(Exopack)、70ミクロン、低密度ポリエチレン、シリコーン化物(Adcoat)
「NeoCarta」、剥離可能なラミネート(Safta)
メッシュ、漉かれた不織布の20gsm(RKWグループ)
「NeoCarta」、剥離可能なラミネート(Safta)、亜硝酸ナトリウム Extra Pure ph Eur, USP メルク社製、脱イオン水(ファースト・ウォーター社))
糖尿病の足潰瘍が形成された患者は以下を含むドレッシングで治療された:
(i) 亜硝酸塩を含んでいる層;および
(ii)水素イオンを含んでいるヒドロゲル。
患者は、長年の糖尿病の62歳の女性で、一年間、彼女の左の足の背部上に潰瘍があった。潰瘍は部分的に直ったがまだ存在した。また、潰瘍を囲む皮膚は腫れて低い質であった。
糖尿病の足潰瘍傷ベッド内の血流は、レーザー・ドップラー フラックスメトリー(Laser Doppler Fluxmetry(LDF))を使用して測定され、還元剤がない状態の中で2部の一酸化窒素を生成するドレッシングを使用して、ベースラインからの著しい増加が見られた。
(i) 亜硝酸塩を含んでいる層;および
(ii)水素イオンを含んでいるヒドロゲルを含むドレッシングシステムによって生産された一酸化窒素の量が、オゾンとの反応の化学発光によってドレッシングシステムから発生されたガスを検知することにより決定された。NO濃度はNOxアナライザー(Thermo、科学的、英国)で決定された。
第一層:傷接触メッシュ(0.1M亜硝酸ナトリウムを含む)
メッシュはSodium Nitrite Extra Pure ph Eur, USP メルク社製からの、1M亜硝酸ナトリウムと脱イオン水の溶液に浸漬されたポリプロピレン・メッシュ(RKWグループ製)である。
亜硝酸ナトリウムは適切なサイズのベッセルへ計量投入され、次に、計量された体積の脱イオン水へ注意深く移される。その後、完全に溶解するまで撹拌され、適切な濃度(0.1M)の溶液を調製した。この実施態様では、亜硝酸ナトリウム溶液はメッシュ(25cm2)上に分配され、次に亜硝酸ナトリウム溶液をメッシュに吸収するための最小時間で、各ペトリ皿に入れられる。完成品は照射によって殺菌される。各メッシュ内にトラップされた亜硝酸塩溶液の重量は、この例においておよそ0.4gだった。
実施例1からのシート・ヒドロゲル(100cm2)は、NOxアナライザーに導くグラス焼結物を覆う、1つのメッシュ(ヒドロゲルに接するメッシュの1cm2あたり15.6mgの亜硝酸塩溶液)、あるいは5つのメッシュ(ヒドロゲルに接するメッシュの1cm2あたり79.2mgの亜硝酸塩溶液)のいずれかの上に置かれた。一酸化窒素の発生は10分間モニターされた。得られたデータは、図4に示される。図4から見ることができるように、生成された一酸化窒素の量は非常に大きかった。また、5つのメッシュを使用した実験において、はるかに長いリリースの期間が観察された。
本発明のドレッシングシステムによって生産された一酸化窒素の量は、オゾンとの反応の化学発光によってドレッシングシステムから発生されたガスを検知することにより決定された。NO濃度はNOxアナライザー(Thermo Scientific, UK)で決定された。
メッシュはSodium Nitrite Extra Pure ph Eur, USP メルク社製からの、1M亜硝酸ナトリウムと脱イオン水の溶液に浸漬されたポリプロピレン・メッシュ(RKWグループ製)である。
亜硝酸ナトリウムは適切なサイズのベッセルへ計量投入され、次に、計量された体積の脱イオン水へ注意深く移される。その後、完全に溶解するまで撹拌され、適切な濃度(0.1Mまたは1.02M)の溶液を調製した。この実施態様では、亜硝酸ナトリウム溶液はメッシュ(25cm2)上に分配され、次に亜硝酸ナトリウム溶液をメッシュに吸収するための最小時間で、各ペトリ皿に入れられる。完成品は照射によって殺菌される。完成品は照射によって殺菌される。各メッシュ内にトラップされた亜硝酸塩溶液の重量は、この例においておよそ0.4gだった。
実施例1からのシート・ヒドロゲル(100cm2)は、NOxアナライザーに導くグラス焼結物を覆う、1つのメッシュ(ヒドロゲルに接するメッシュの1cm2あたり15.6mg、0.1Mの亜硝酸塩溶液)、あるいは1つのメッシュ(ヒドロゲルに接するメッシュの1cm2あたり15.6mg、1.02Mの亜硝酸塩溶液)のいずれかの上に置かれた。一酸化窒素の発生は10分の時限上にモニターされた。得られたデータは、図5に示される。図5の中のデータは、リリースの量が酸性化シート・ヒドロゲルとの接触のエリアへ拘束された亜硝酸ナトリウム溶液の濃度に依存することを示す。
これは、WO 02/17881の例8に示されたデータの簡略版で、本発明に従わない一酸化窒素生成システムを使用した研究について記述する。
VRS痛み分類は中央のスコアに著しい差を記録した(図6)。活性治療薬は、プラセボ治療薬より、カニューレ挿入への疼痛反応のより大きな減少に帰着した(p<0.0001)。活性配合物は、さらに40.3%(p<0.001)の平均VAS痛みスコアの統計的に有意な減少を発生させた。
Claims (15)
- (i) 亜硝酸塩を含んでいる層;および
(ii)水素イオンを含んでいるヒドロゲル;を含み、
亜硝酸塩を含む層および/またはヒドロゲルが、薬学的に有効な薬品を含むシステムであって、Cu2+、Zn2+および/またはFe2+イオンの源を含まないドレッシングシステム。 - 層は溶解可能なフィルムであることを特徴とする請求項1に記載のドレッシングシステム。
- 溶解可能なフィルムは、ポリビニルアルコール、ポリビニルピロリドン、セルロースに基づいたポリマーまたはセルロースから作られることを特徴とする請求項2に記載のドレッシングシステム。
- 層はメッシュであることを特徴とする請求項1に記載のドレッシングシステム。
- メッシュはポリマーから作られることを特徴とする請求項4に記載のドレッシングシステム
- ポリマーはポリプロピレンであることを特徴とする請求項5に記載のドレッシングシステム。
- 亜硝酸塩はアルカリ金属亜硝酸塩あるいはアルカリ土類金属亜硝酸塩であることを特徴とする、請求項1から6のいずれか1項記載のドレッシングシステム。
- 亜硝酸塩は亜硝酸ナトリウムであることを特徴とする、請求項7記載のドレッシングシステム。
- (a)システムは亜硝酸塩を含んでいる複数の層を含み、および/または
(b)亜硝酸塩は亜硝酸塩溶液として存在することを特徴とする、請求項1から8のいずれか1項記載のドレッシングシステム。 - (a)ヒドロゲルは部分的に水和される、および/または
(b)ヒドロゲルは架橋されている、および/または
(c)ヒドロゲルはコポリマーであることを特徴とする、請求項1から9のいずれか1項記載のドレッシングシステム。 - 前記(c)のヒドロゲルはポリスルフォナートとアクリル酸のコポリマーであることを特徴とする、請求項10に記載のドレッシングシステム。
- システムはチオールまたは還元剤を含まないことを特徴とする、請求項1から11のいずれか1項記載のドレッシングシステム。
- 医学で使用される、請求項1から12のいずれか1項記載のドレッシングシステム。
- 薬学的に有効な薬品はリグノカイン(リドカイン)、アメトカイン(テトラカイン)、キシロカイン、ブピカイン、ピリロカイン、ロピバカイン、ベンゾカイン、メピバカイン、コカインあるいはその混合物から成る群から選ばれた麻酔薬であることを特徴とする、痛みの治療で使用される、請求項1から12のいずれか1項記載のドレッシングシステム。
- 痛みの治療は局部麻酔であることを特徴とする請求項14に記載のドレッシングシステム。
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GB201309092A GB201309092D0 (en) | 2013-05-20 | 2013-05-20 | Transdermal delivery system |
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EP1100557B1 (en) | 1998-07-31 | 2006-12-06 | First Water Limited | Bioadhesive compositions comprising hydrophobic polymers |
GB9905425D0 (en) | 1999-03-09 | 1999-05-05 | Queen Mary & Westfield College | Pharmaceutical composition |
GB0021317D0 (en) * | 2000-08-30 | 2000-10-18 | Queen Mary & Westfield College | Transdermal pharmaceutical delivery composition |
CA2323382C (en) | 2000-10-17 | 2004-04-13 | Pharma Mag Inc. | Wound dressing |
GB0715554D0 (en) * | 2007-08-09 | 2007-09-19 | Insense Ltd | Improvements relating to skin dressings |
GB0715556D0 (en) | 2007-08-09 | 2007-09-19 | Insense Ltd | Improvements relating to skin dressings |
US20100055161A1 (en) | 2008-08-27 | 2010-03-04 | Dong June Ahn | Hydrogel face mask for delivering skin care agents |
IN2012DN03428A (ja) * | 2009-10-14 | 2015-10-23 | Theravasc Inc | |
JP2013515021A (ja) | 2009-12-22 | 2013-05-02 | リスホスピタレト,コペンハーゲン ユニバーシティ ホスピタル | 創傷治療製品 |
GB201309091D0 (en) * | 2013-05-20 | 2013-07-03 | Edixomed Ltd | Dressing system |
-
2013
- 2013-05-20 GB GB201309092A patent/GB201309092D0/en not_active Ceased
-
2014
- 2014-05-20 CN CN201480029019.7A patent/CN105431175B/zh active Active
- 2014-05-20 PL PL14727614T patent/PL2908873T3/pl unknown
- 2014-05-20 LT LTEP14727614.1T patent/LT2908873T/lt unknown
- 2014-05-20 US US14/892,218 patent/US10010648B2/en active Active
- 2014-05-20 SI SI201430560T patent/SI2908873T1/en unknown
- 2014-05-20 HU HUE14727614A patent/HUE035847T2/en unknown
- 2014-05-20 RS RS20180044A patent/RS56833B1/sr unknown
- 2014-05-20 AU AU2014270116A patent/AU2014270116B2/en active Active
- 2014-05-20 WO PCT/GB2014/051544 patent/WO2014188175A1/en active Application Filing
- 2014-05-20 NO NO14727614A patent/NO2908873T3/no unknown
- 2014-05-20 JP JP2016514478A patent/JP6446035B2/ja active Active
- 2014-05-20 DK DK14727614.1T patent/DK2908873T3/en active
- 2014-05-20 PT PT147276141T patent/PT2908873T/pt unknown
- 2014-05-20 EP EP14727614.1A patent/EP2908873B1/en active Active
- 2014-05-20 ES ES14727614.1T patent/ES2658037T3/es active Active
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Also Published As
Publication number | Publication date |
---|---|
GB201309092D0 (en) | 2013-07-03 |
WO2014188175A1 (en) | 2014-11-27 |
AU2014270116A1 (en) | 2015-12-10 |
PL2908873T3 (pl) | 2018-06-29 |
ES2658037T3 (es) | 2018-03-08 |
AU2014270116B2 (en) | 2017-12-21 |
SI2908873T1 (en) | 2018-04-30 |
LT2908873T (lt) | 2018-02-12 |
PT2908873T (pt) | 2018-01-23 |
US20160089473A1 (en) | 2016-03-31 |
RS56833B1 (sr) | 2018-04-30 |
CN105431175A (zh) | 2016-03-23 |
US10010648B2 (en) | 2018-07-03 |
DK2908873T3 (en) | 2018-01-22 |
EP2908873B1 (en) | 2017-10-18 |
HUE035847T2 (en) | 2018-05-28 |
CN105431175B (zh) | 2018-12-28 |
HRP20180079T1 (hr) | 2018-04-06 |
NO2908873T3 (ja) | 2018-03-17 |
EP2908873A1 (en) | 2015-08-26 |
JP2016518458A (ja) | 2016-06-23 |
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