JP5731446B2 - 局所用生体付着性製剤 - Google Patents
局所用生体付着性製剤 Download PDFInfo
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- JP5731446B2 JP5731446B2 JP2012156518A JP2012156518A JP5731446B2 JP 5731446 B2 JP5731446 B2 JP 5731446B2 JP 2012156518 A JP2012156518 A JP 2012156518A JP 2012156518 A JP2012156518 A JP 2012156518A JP 5731446 B2 JP5731446 B2 JP 5731446B2
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Description
本発明の前製剤に調合される生理活性物質の量は、機能的な投薬量と、投与時に形成されるデポー組成物が持続放出をもたらすべき期間とに依存する。典型的には、ある特定の作用物質に関して規定される投与量は、標準的な単回投与量に、前記製剤がもたらすことが期待される作用持続期間の長さに応じて回数を乗じたものに相当する量程度とされる。明らかなことではあるが、この量は、大量投与の副作用を考慮して治療開始時に調整する必要があり、よって、これが通常使用される最大投与量となる。いずれの場合にも適した正確な量は、適切な実験によって容易に決定される。
i. ベンジダミン(局所鎮痛剤、抗炎症剤)またはその他の局所鎮痛剤、鎮痛剤、抗炎症剤、抗菌剤、抗真菌剤、またはこれらの組み合わせ。組成物は、例えば、口腔粘膜炎(例えば、化学療法および放射線療法によって引き起こされるもの)に罹患する患者の口腔内粘膜、特に損傷、感作、感染粘膜に持続効果をもたらす。特に、口腔粘膜炎の治療用。
ii. トラマドール(鎮痛剤)。持続的な全身鎮痛効果を有する組成物を提供する。
iii. 歯根膜感染症および局所感染症治療用のグルコン酸クロルヘキシジン(抗菌剤)。特に、歯周ポケットにおける長時間作用効果のために用いられる。組成物は、液体の形態で適用されると、生体付着性のゲルをin situ形成し、クロルヘキシジンを1時間よりも長い時間、好ましくは6時間よりも長い時間、最も好ましくは24時間よりも長い時間にわたって放出するデポーを生成する。表面ゲル形成時間は、1秒〜5分の間であることが確認された。
i. フェンタニル(鎮痛剤)は、鼻腔または口腔にスプレーとして投与されると、迅速に発現し、かつ持続期間沈痛をもたらす。
ii. ジアゼパム(抗不安剤)は、全身的効果を有し、効果の迅速な発現と持続期間をもたらす非腸管外、鼻腔、または口腔デポーを提供する。スプレーとして投与される。
i. 持続期間を有するジクロフェナク(NSAID)。in situ相形成液として投与される。
ii. 緑内障治療用のピロカルピン(副交感神経刺激剤(parasymptomimetic)、コリン作動薬)
iii アレルギー性結膜炎軽減効果が長続きし、再適用までの間隔が長い点眼液を提供する塩酸レボカバスチン、フマル酸ケトチフェン
iv シェーグレン症候群の治療のための塩酸ピロカルピン
v デキサメタゾン、(コルチコステロイド)
vi クロラムフェニコール(主として静菌性の抗感染薬)
vii インドメタシン(NSAID)
デポーi〜viiは、眼の表面に直接適用する液体スプレー、またはより好ましくは液滴として調合され、涙によって洗い流されることや、まばたき/眼をこすることによる摩耗に対して高い耐性を有するin situデポー構成物を提供する。本発明の組成物は、眼科的用途に対し優れた適合性を示す。ウサギモデルにおける安全性試験の結果、過敏反応およびかすみ目といった影響は見られなかった。ここでは適切か?
眼科用組成物に好適なその他の活性物質としては、抗ヒスタミン剤、マスト細胞安定剤、非ステロイド系抗炎症剤(NSAID)、コルチコステロイド(例えば、アレルギー性結膜炎の治療用)、流入(inflow)抑制/阻害剤(β遮断薬:チモロール、ベタキソロール、カルテオロール、レボブノロール等、局所用炭酸脱水酵素阻害剤:ドルゾラミド、ブリンゾラミド、交感神経刺激剤:エピネフリン、ジピベフリン、クロニジン、アプラクロニジン、ブリモニジン)、流出(outflow)促進剤(副交感神経刺激剤(コリン作動薬):ピロカルピンプロスタグランジン類似体、ならびに関連化合物:ラタノプロスト(atanoprost)、トラボプロスト、ビマトプロスト、ウノプロストン)を含む抗緑内障活性物質が挙げられる。
i. アシクロビル(抗ウイルス薬)。組成物は、持続期間を有する生体付着性の膜形成物を生成する。スプレーまたは液体として適用される。
ii. ウンデカン酸テストステロンまたはエナント酸テストステロン(testosterone enantate)(ホルモン欠乏症)。持続期間を有する生体付着性の膜形成組成物。エアゾールもしくはポンプスプレー、または液体として適用してもよい。
図2は、N−メチルピロリジノン(N-methyl pyrolidinone)(NMP)およびEtOHの添加による、前製剤の粘度の非線形の低下を示している。
図3は、クロルヘキシジンを、5%の薬剤量に相当する製剤1g中50mgの濃度で含有するPC/GDO/EtOH(36/54/10重量%)を含むデポー製剤からの、過剰量の水相へのクロルヘキシジンのインビトロ放出を示している。
ホスファチジルコリン(「PC」−エピクロン(Epikuron)200)とグリセロールジオレアート(GDO)を異なる割合で含有し、さらにEtOHを溶媒として含有する注射製剤を調製し、デポー前駆体製剤を過剰量の水で平衡化した後、各種液晶相が利用可能であることを例証した。
水溶性着色剤であるメチレンブルー(MB)を、製剤1g中11mgの濃度となるように製剤C(実施例1参照)に分散させた。前記製剤0.5gを100mlの水に注入したところ、硬い逆ヘキサゴナルHII相が形成された。水相に放出されたMBの吸光度を、10日間にわたり664nmで観察した。放出の観察は、エレンマイヤーフラスコ内において、37℃で、低磁力攪拌を行いながら実施した。
PC/GDO/EtOHの混合物を、実施例1に記載の方法で製造した。ロータリーエバポレーター(真空、40℃、1時間)を用いて前記混合物からEtOHを完全またはほぼ完全に除去し、この結果得られた固体混合物をガラスバイアルで計量した後、2、5、10、または20%の溶媒(EtOH、プロピレングリコール(PG)、またはn−メチルピロリドン(NMP))を添加した。これら試料を数日間平衡化させた後、フィジカ(Physica) UDS 200レオメータを用い、0.1s-1の剪断速度で、25℃で粘度を測定した。
実施例1に記載の方法により、表2に示す組成で製剤を製造した。活性物質(ペプチド)であるサケカルシトニン(sCT)を、製剤1g中sCTが500μgの濃度となるように各製剤に添加した。前記製剤は、非経口投与用の均一懸濁液として設計した(前記薬剤はPC/GDO/EtOH系に完全には溶解されないため、使用の直前に混合する必要がある)。
注射製剤を得て、当該系を通常の注射器で投与可能とするため、各種溶媒によって粘度を低下させることが時として必要である(実施例3参照)。粘度低下用溶媒によってもたらされる別の重要な効果は、製剤を濾過滅菌できることである。
製剤の組成と活性物質の性質および濃度によっては、特定の溶媒が好ましい場合がある。
ベンジダミンは、非ステロイド系抗炎症剤であり、炎症疾患の局所薬剤として広く使用されている。
実施例1の方法を用い、表3に示す数種の異なるGDO品質(デンマーク、ダニスコ(Danisco)社提供)でデポー前駆体製剤を調製した。最終的なデポー前駆体は、PCを36重量%、GDOを54重量%、EtOHを10重量%含有していた。前記デポー前駆体の外観は、使用した品質のばらつきの影響を受けておらず、また、過剰量の水との接触後に、逆ミセルキュービック相挙動(I2構造)を有するモノリスが形成された。
飽和炭化水素鎖を含む様々な量のPCを用い、実施例1で調製したようなPC/GDO/EtOHの混合物にエピクロン 200SHを直接添加することにより、デポー前駆体製剤を調製した。これらの製剤を表4に示している。前駆体製剤は全て、室温(RT)において均一な一相の試料であり、エピクロン 200SHの量の増加と共にその粘度が上昇した。前記デポー前駆体を過剰量の水に注入すると、逆ミセルキュービック(I2)構造を備えたモノリスが生じた。より多量のエピクロン 200SHを含有する試料から形成されたモノリスは不透明となったが、これは、おそらくは、水に曝露されてI2相が形成されたことにより、エピクロン 200SHとそれ以外の成分とが分離したことを示している。
ポンプスプレーボトルは、製剤を局所的に、例えば、皮膚または口腔粘膜に適用する上で便利な手段であることがわかった。
実施例10に記載のデポー前駆体製剤(PC36重量%、GDO54重量%、およびEtOH10重量%)を皮膚に適用した後、適用した製剤を10分間流水(10リットル/分)に曝した。前記製剤は優れた生体付着特性と水洗に対する耐性を示し、前記製剤の損失は認められなかった。
実施例1に記載のように調製したデポー前駆体製剤(PC36重量%、GDO54重量%、およびEtOH10重量%)を、少なくとも3時間、空気(室温(RT)、相対湿度40%)に曝露した後、固体キュービック相が形成された。このキュービック相構造の形成は、局所膜は、過剰量の水性流体に直接曝露しなくとも、適用後にバルク非ラメラデポー特性を獲得することを実証している。
歯周炎またはインプラント周囲炎を治療するため、抗菌製剤を歯周ポケットに注入する。通常、当該製剤の持続効果が所望される。
実施例1に記載のように調製し、かつ抗菌性界面活性物質であるガルドール(Gardol)(グリシン、N−メチル−N−(1−オキソドデシル)−、ナトリウム塩)(PC/GDO/EtOH/ガルドール(34/51/10/5))を含有させた製剤を、別の抗菌製剤として提供した。この製剤をラットの歯周ポケットに注入する。
インプラント周囲炎を治療するためには、生体表面への付着のみならず、金またはチタンインプラント等の高エネルギー表面に対する付着も重要である。さらに、製剤がセラミックおよびプラスチック表面に付着することも重要である。
齲蝕の発現に対抗するため、フッ化物含有化合物がしばしば必要とされる。デポー効果を有する生体付着性の製剤前駆体を、PC/GDO/EtOH/フッ化ナトリウム(35/53/10/2)の混合物から、実施例1に示すように調製した。製剤は前記前駆体に溶解できないため、前記製剤は、フッ化ナトリウムの分散液であった。当該液体製剤を、ブラシを用いて歯に適用した。唾液を取り込むことにより、前記製剤は固化し、長期間(数時間)にわたるフッ化ナトリウムの持続放出を行うデポーを形成した。
口腔内に適した局所デポー系とするため、PC/GDOの比率を低下させることにより、当該系の機械的性質を調整した。
ピペットを用いた口腔内への適用に適したものとするためには、製剤の固化/粘性化を、スプレー製剤と比べて遅らせる必要がある。これは、適用後に製剤を口腔内において舌で簡便に薄膜状に広げることを可能にするためである。
実施例18の混合物を、爪床および足指間に噴霧した。前記製剤は、水性流体(汗参照)の取り込みによりゆっくりと固化/粘性化する。スプレーで適用した後に水を添加することにより、固化の速度を上げることができる。前記製剤は、優れた生体付着特性を有し、数時間の持続期間を有していた。
表5に明記した組成の製剤を、実施例1に記載の方法を用いて調製した。前記製剤0.5gに、過剰量のベンジダミン(50mg)を添加した。15℃の振盪器上にバイアルを3日間配置し、その後、溶液をフィルター(0.45μm)にかけ、溶解されなかったベンジダミンの結晶を除去した。各製剤におけるベンジダミン濃度を、逆相グラジエントHPLCおよび306nmでのUV検出によって求めた。結果を表5に示す。
数種類の異なるPC/α−トコフェロール組成物を用いて、実施例1の方法(まず、PCを適量のEtOHに溶解し、その後、α−トコフェロールを添加して透明な均一溶液とする)により、デポー前駆体製剤を調製した。
水溶性着色剤であるフルオレセイン二ナトリウム(Fluo)を、製剤1g中Fluo5mgの濃度となるように、PC/α−トコフェロール/エタノール(27/63/10重量%)を含有する製剤に溶解した。前記製剤0.1gを2mlのリン酸緩衝食塩水(PBS)に注入したところ、逆ミセル(I2)相が形成された。前記水相に放出されたFluoの吸光度を、3日間にわたり490nmで観察した。放出の調査は、アルミニウム製の完全引き剥がし式キャップ(fully tear off cap)で蓋をした3mlのバイアル内において、37℃で実施した。前記バイアルを、150rpmの振動台上に配置した。
ベンジダミンを、GDO、PC、エタノール、および任意にPG/APを以下の割合で含む混合物と混合することにより、実施例1に記載のように製剤を調製した。
麻薬性鎮痛剤であるフェンタニルを、GDO、PC、エタノール、および任意にPGを以下の割合で含む混合物と混合することにより、実施例1に記載のように製剤を調製した。
ベンゾジアゼピン系抗不安剤であるジアゼパムを、GDO、PC、エタノール、および任意にPGを以下の割合で含む混合物と混合することにより、上述の実施例に記載のように製剤を調製した。
半合成抗生物質であるクリンダマイシン(遊離塩基または塩)を、GDO、PC、エタノール、およびPGを以下の割合(重量)で含む混合物と混合することにより、上述の実施例に記載のように製剤を調製した。
PC/GDOおよび共溶媒の混合物を、以下の表に示す割合で、実施例1および実施例3に記載の方法によって調製した。
数種類のUV吸収/散乱剤のそれぞれを、GDO、PC、およびエタノールを以下の割合(重量)で含む混合物と混合することにより、実施例1に記載のように製剤を調製した。
抗感染剤であるクロルヘキシジンジグルコナートを、GDO、PC、およびエタノールを以下の割合(重量)で含む混合物と混合することにより、実施例1に記載のように製剤を調製した。
ジクロフェナクナトリウムは、非ステロイド系抗炎症剤(NSAID)である。ジクロフェナクナトリウムはフェニル酢酸基に属し、各種病因による炎症疾患、変性関節疾患、ならびにこれら以外の多くの疼痛を伴う疾患に使用される。
実施例30のジクロフェナクナトリウム含有製剤を1滴、3mlの食塩水にピペットで添加した。凝集性の液晶相が形成された。
実施例30のジクロフェナクナトリウム含有製剤を1滴、健常人の腕の皮膚に適用し、約2〜4cm2の面積を覆う薄膜となるように塗りつけた。適用後間もなく、前記液体製剤は、皮膚および/または空気中から少量の水分を取り込むことにより、はるかに強固な膜となった。
実施例30の表に示す組成のプラシーボ製剤を、標準的なポンプ-スプレーボトルに充填した。前記ポンプを製剤を用いてプライミングした後、前記製剤を、準最適な噴霧パターンで皮膚に適用することができた。
実施例30の表に示す組成のプラシーボ製剤を、標準的な圧縮ポンプボトルに充填した。このデバイスでは、良好なミスト/エアゾールおよび噴霧パターンが得られた。前記製剤を健常人の腕の皮膚に噴霧したところ、皮膚および/または空気中から少量の水分を取り込んだ後、強固な膜が形成された。
実施例30の表に示す組成のプラシーボ製剤を、炭化水素噴霧剤または噴霧剤であるHFC−134aのいずれかと共に、圧力駆動噴霧デバイスに充填した。いずれの噴霧剤も、前記製剤と共に低粘度の均一な混合物を形成することがわかった。前記製剤を健常人の腕の皮膚に噴霧したところ、皮膚および/または空気中から少量の水分を取り込んだ後、強固な膜が迅速に形成された。
以下の表に示す組成の製剤を、ロータリーエバポレーター(真空、40℃)を用いて実施例30の表に示す組成のプラシーボ製剤からEtOHを蒸発させることによって調製した。この結果得られた製剤は高粘度であったが、噴霧剤(炭化水素噴霧剤またはHFC−134a)と混合してスプレーボトルに充填すると、前記製剤を健常人の腕の皮膚に噴霧することができ、皮膚および/または空気中から少量の水分を取り込んだ後、この皮膚上に強固な膜が形成された。
製剤中におけるPC/GDO比率を変更することにより、口腔内の異なる場所での前記製剤の持続時間を調整することができた。PC/GDO/EtOH(36/54/10)という組成の製剤は、歯等の硬質な表面に付着しやすく、一方、PC/GDO/EtOH(27/63/10)という組成の製剤は、上口蓋により適していることがわかった。
前駆体中の活性物質の溶解度を向上させるためには、製剤中の溶媒を変更することが有用な場合がある。多数の異なる溶媒混合物を製剤前駆体中に使用し(表参照)、過剰量の水溶液と接触させた後のこれらの液晶相形成能について調べた。各製剤を1滴、3mlの食塩水にピペットで添加した。使用した溶媒(混合物)とは無関係に、凝集性の液晶相が形成された。
以下の表に示す成分を混合することにより、2%エナント酸テストステロンを含有する局所製剤を調製した。当該液体製剤を皮膚に適用して間もなく、前記製剤は、皮膚および/または空気中から少量の水分を取り込むことにより、はるかに強固な膜となった。
Claims (40)
- a)少なくとも1種のトコフェロールと、
b)少なくとも1種の、少なくとも50%のホスファチジルコリンからなるリン脂質と、
c)少なくとも1種の、エタノールを含む生体適合性有機溶媒2〜30重量%との低粘度混合物を含む製剤であって、
成分a:bの重量比が、85:15〜30:70であり、
水性流体および/または体表面との接触により、少なくとも1つの生体付着性な液晶相構造を形成し、
粘度が20℃において0.1〜5000mPasである
製剤。 - 成分a)が、少なくとも1種の中性ジアシル脂質をさらに含む請求項1に記載の製剤。
- 前記低粘度混合物中に溶解するかまたは分散させた生理活性物質を少なくとも1種類含む請求項1または2に記載の製剤。
- 前記ジアシル脂質が、ジアシルグリセロールから成る、請求項2に記載の製剤。
- 前記ジアシル脂質が、グリセロールジオレアートから成る、請求項4に記載の製剤。
- 成分b)が、ホスファチジルコリンである、請求項1〜5のいずれか一項に記載の製剤。
- 分子性溶液、L2および/またはL3相構造を有する、請求項1〜6のいずれか一項に記載の製剤。
- a)を35〜60重量%、b)を20〜50重量%、およびc)を10〜20重量%含有する、請求項1〜7のいずれか一項に記載の製剤。
- 成分c)がアルコールである、請求項1〜8のいずれか一項に記載の製剤。
- a)+b)の重量の10%までの荷電両親媒性物質をさらに含有する、請求項1〜9のいずれか一項に記載の製剤。
- 前記活性物質が、コルチコステロイド;非ステロイド系抗炎症性化合物;メトトレキサート、アザチオプリンおよび6−メルカプトプリンからなる群から選択される炎症経路の局所阻害剤;ホスホリパーゼ阻害剤;抗酸化剤;抗感染剤;サイトカインおよびサイトカイン誘発因子/抑制因子(supressors)から選択される、請求項1〜10のいずれか一項に記載の製剤。
- 洗浄、噴霧、またはうがいにより投与可能である、請求項1〜10のいずれか一項に記載の製剤。
- ベンジダミンを含有する、請求項12に記載の製剤。
- 生体付着性制御放出製品を形成する口腔内投与用の請求項3〜12のいずれか一項に記載の局所用製剤であって、前記活性物質が、ベンジダミン、トラマドール、アセトアミノフェン、イブプロフェン、プロポキシフェン、コデイン、ジヒドロコデイン、ヒドロコドン、オキシコドン、ナルブフィン、メペリジン、レボルファノール(Leverorphanol)、ヒドロモルホン、オキシモルホン、アルフェンタニル、フェンタニル、およびスフェンタニル(Sefentanil)から選択される少なくとも一つを含む、局所用製剤。
- 皮膚疾患、眼疾患、生殖器痛、指および/または足指の爪の感染および疾患ならびに、体表面における炎症(imflammation)および/または過敏反応を治療するための、
a)少なくとも1種のトコフェロールと、
b)少なくとも1種の、少なくとも50%のホスファチジルコリンからなるリン脂質と、
c)少なくとも1種の、エタノールを含む生体適合性の有機溶媒2〜30重量%との低粘度混合物を含む局所用製剤。 - 体表面および/または体腔における、炎症および/または過敏反応を治療するための請求項15に記載の局所用製剤。
- 口腔粘膜炎または炎症性腸疾患の治療のための請求項15に記載の局所用製剤。
- 歯根膜感染症および局所感染症治療用の口腔内投与に適した請求項15に記載の局所用製剤であって、前記活性物質が、グルコン酸クロルヘキシジンであり、前記製剤が、適用後、1秒〜5分間で表面ゲルをin situ形成する液体製品として適用される、局所用製剤。
- 経眼投与に適した請求項15に記載の局所用製剤であって、前記活性物質が、ジクロフェナク、ピロカルピン、塩酸レボカバスチン、フマル酸ケトチフェン、チモロール、ベタキソロール、カルテオロール、レボブノロール、ドルゾラミド、ブリンゾラミド、エピネフリン、ジピベフリン、クロニジン、アプラクロニジン、ブリモニジン、ピロカルピン、ラタノプロスト(atanoprost)、トラボプロスト、ビマトプロスト、ウノプロストン、塩酸ピロカルピン、デキサメタゾン、クロラムフェニコール、およびインドメタシンから選択される少なくとも一つを含む、局所用製剤。
- 生体付着性制御放出製品を形成する経皮投与用の請求項15に記載の局所用製剤であって、前記活性物質が、化粧剤、香料、香味料、精油、UV吸収剤、およびその混合物から選択される、局所用製剤。
- ヒト以外の動物の身体への生理活性物質の送達方法であって、
この方法が、
a)少なくとも1種のトコフェロールと、
b)少なくとも1種の、少なくとも50%のホスファチジルコリンからなるリン脂質と、
c)少なくとも1種の、エタノールを含む生体適合性有機溶媒2〜30重量%との非液晶低粘度混合物を含む製剤を投与することを含み、
成分a:bの重量比が、85:15〜30:70であり、
少なくとも1種の生理活性物質が前記低粘度混合物に溶解または分散しており、投与後にインビボでの水性流体との接触により少なくとも1つの液晶相構造が形成され、
粘度が20℃において0.1〜5000mPasである送達方法。 - 体表面および/または体腔内における炎症および/または過敏反応の治療のための、
a)少なくとも1種のトコフェロールと、
b)少なくとも1種の、少なくとも50%のホスファチジルコリンからなるリン脂質と、
c)少なくとも1種の、エタノールを含む生体適合性有機溶媒2〜30重量%との非液晶低粘度混合物を含み、
成分a:bの重量比が、85:15〜30:70であり、
投与後にインビボでの水性流体との接触により少なくとも1つの液晶相構造が形成され、
粘度が20℃において0.1〜5000mPasである
製剤。 - 前記低粘度混合物中に溶解するかまたは分散させた生理活性物質を少なくとも1種類含む請求項22に記載の製剤。
- 成分a)が、少なくとも1種の中性ジアシル脂質を更に含む請求項22または23に記載の製剤。
- 前記ジアシル脂質が、ジアシルグリセロールから成る、請求項24に記載の製剤。
- 前記ジアシル脂質が、グリセロールジオレアートから成る、請求項25に記載の製剤。
- 成分b)が、ホスファチジルコリンからなる、請求項22〜25のいずれか一項に記載の製剤。
- 分子性溶液、L2および/またはL3相構造を有する、請求項22〜27のいずれか一項に記載の製剤。
- a)を35〜60重量%、b)を20〜50重量%、およびc)を10〜20重量%含有する、請求項22〜28のいずれか一項に記載の製剤。
- 成分c)がエタノールを含むアルコールからなる、請求項22〜28のいずれか一項に記載の製剤。
- 前記活性物質が、コルチコステロイド;非ステロイド系抗炎症性化合物;メトトレキサート、アザチオプリンおよび6−メルカプトプリンからなる群から選択される炎症経路の局所阻害剤;ホスホリパーゼ阻害剤;抗酸化剤;抗感染剤;サイトカインおよびサイトカイン誘発因子/抑制因子(supressors)から選択される、請求項22〜30のいずれか一項に記載の製剤。
- 洗浄、噴霧、またはうがいにより投与可能である、請求項22〜31のいずれか一項に記載の製剤。
- ベンジダミンを含有する、請求項22〜32に記載の製剤。
- 前記炎症が、クローン病、潰瘍性大腸炎(ulcerative collitus)、または口腔粘膜炎により引き起こされる、請求項22〜33のいずれかに記載の製剤。
- 生体付着性制御放出製品を形成する口腔内投与用の請求項22〜33のいずれかに記載の局所用製剤であって、前記生理活性物質が、ベンジダミン、トラマドール、アセトアミノフェン、イブプロフェン、プロポキシフェン、コデイン、ジヒドロコデイン、ヒドロコドン、オキシコドン、ナルブフィン、メペリジン、レボルファノール(Leverorphanol)、ヒドロモルホン、オキシモルホン、アルフェンタニル、フェンタニル、およびスフェンタニル(Sefentanil)から選択される1以上を含む製剤。
- 歯根膜感染症および局所感染症治療用の口腔内投与に適した請求項22〜33のいずれか一項に記載の局所用製剤であって、前記活性物質が、グルコン酸クロルヘキシジンであり、前記製剤が、適用後、1秒〜5分間で表面ゲルをin situ形成する液体製品として適用される、局所用製剤。
- 経眼投与に適した請求項22〜33のいずれか一項に記載の局所用製剤であって、前記活性物質が、ジクロフェナク、ピロカルピン、塩酸レボカバスチン、フマル酸ケトチフェン、チモロール、ベタキソロール、カルテオロール、レボブノロール、ドルゾラミド、ブリンゾラミド、エピネフリン、ジピベフリン、クロニジン、アプラクロニジン、ブリモニジン、ピロカルピン、ラタノプロスト(atanoprost)、トラボプロスト、ビマトプロスト、ウノプロストン、塩酸ピロカルピン、デキサメタゾン、クロラムフェニコール、およびインドメタシンから選択される少なくとも一つを含む、局所用製剤。
- 生体付着性制御放出製品を形成する経皮投与用の請求項22〜33のいずれか一項に記載の局所用製剤であって、前記活性物質が、化粧剤、香料、香味料、精油、UV吸収剤、およびその混合物から選択される、局所用製剤。
- 前記炎症が、クローン病、潰瘍性大腸炎(ulcerative collitus)、または口腔粘膜炎により引き起こされる、請求項22〜38のいずれかに記載の局所用製剤。
- ヒトまたは動物である対象における口腔粘膜炎の治療のための請求項22〜38のいずれかに記載の製剤であって、前記製剤が、40〜60重量%のグリセロールジオレアート、20〜35%のホスファチジルコリン、5〜25%のエタノール、および1〜8%のベンジダミン、またはベンザミンの誘導体を含む製剤。
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GB0507811.8 | 2005-04-18 | ||
PCT/GB2005/002217 WO2005117830A1 (en) | 2004-06-04 | 2005-06-06 | Liquid depot formulations |
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AT (1) | ATE462409T1 (ja) |
DE (1) | DE602005020359D1 (ja) |
DK (1) | DK1845942T3 (ja) |
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DE602005020359D1 (de) | 2010-05-12 |
JP2012214494A (ja) | 2012-11-08 |
US20090155193A1 (en) | 2009-06-18 |
PL2206495T3 (pl) | 2013-05-31 |
US20090170782A1 (en) | 2009-07-02 |
US9757461B2 (en) | 2017-09-12 |
US9968680B2 (en) | 2018-05-15 |
SI1845942T1 (sl) | 2014-06-30 |
ES2458992T3 (es) | 2014-05-07 |
ATE462409T1 (de) | 2010-04-15 |
EP2206495B1 (en) | 2012-11-21 |
ES2400034T3 (es) | 2013-04-05 |
US20150147282A1 (en) | 2015-05-28 |
ES2343641T3 (es) | 2010-08-05 |
EP2206495A1 (en) | 2010-07-14 |
US8920782B2 (en) | 2014-12-30 |
US20140219935A1 (en) | 2014-08-07 |
DK1845942T3 (da) | 2014-04-28 |
US20180078647A1 (en) | 2018-03-22 |
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