JP2015509924A - 涙膜安定性における改善 - Google Patents
涙膜安定性における改善 Download PDFInfo
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- JP2015509924A JP2015509924A JP2014555040A JP2014555040A JP2015509924A JP 2015509924 A JP2015509924 A JP 2015509924A JP 2014555040 A JP2014555040 A JP 2014555040A JP 2014555040 A JP2014555040 A JP 2014555040A JP 2015509924 A JP2015509924 A JP 2015509924A
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- tear film
- meibum
- inflammatory
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Abstract
Description
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面に化合物を提供して、マイバム産生組織によるコレステロールの合成を低減することによって、
前記個人の涙膜を安定化し、又は涙膜の安定性を改善し、又は涙膜破壊時間を延長する。
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面に化合物を提供して、マイバム産生組織によるコレステロールの合成を低減し、
前記個人の眼表面に抗炎症化合物及び/又は免疫抑制剤を提供することによって、
前記個人の涙膜を安定化する。
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面にHMG CoA還元酵素阻害剤を提供して、マイバム産生組織によるコレステロールの合成を低減することによって、
前記個人の涙膜を安定化する。
後部眼瞼炎を有する個人を提供し、
治療的有効量のHMG CoA還元酵素阻害剤を前記個人の眼表面に提供することによって、
前記個人の後部眼瞼炎を処置する。
後部眼瞼炎を有する個人を提供し、
治療的有効量のアトルバスタチンを前記個人の眼表面に提供することによって、
前記個人の後部眼瞼炎を処置する。
「涙層」、「前眼涙液膜」、「涙液層」及び「角膜前膜」としても既知の「涙膜」は、概して、角膜の前表面を覆う組成物を指し、該組成物は、涙液と、マイボーム腺及び結膜腺の分泌物とからなる。涙膜は、3つの層から構成されている:(1)ムチン層(又は粘膜層);(2)涙層(又は水性層)及び(3)油性層(又は脂質層)。最も内側の水性層及びムチンゲル層を単一の層として見なす者もいる。
本明細書に記載した臨床試験において、本発明者らは、眼瞼炎、特に後部眼瞼炎の1つ以上の所見を有する様々な個人を処置した。この試験は、各個人における涙膜安定性の有意な改善を示した。
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面に化合物を提供して、マイバム産生組織によるコレステロールの合成を低減することによって、
前記個人の前記涙膜を安定化する。
個人の眼表面に抗炎症化合物及び/又は免疫抑制剤を提供する
ステップを含む。
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面に、ホルモン又はアンドロゲンの形態の化合物を提供して、マイバム産生組織によるコレステロールの合成を低減し、
前記個人の眼表面に抗炎症化合物及び/又は免疫抑制剤を提供することによって、
前記個人の涙膜を安定化する。
個人の眼表面に抗生物質を提供する
更なるステップを含んでもよい。
本発明はまた、組成物、特に、溶液又は懸濁液、局所軟膏、及びインサートを含む、眼科投与に適合された組成物にも関し、それらの例は以下に記載する。
本明細書に記載した組成物は、更に、薬学分野にて慣習的な、薬学的に許容され得る賦形剤を含有してもよい。そのような薬学的に許容され得る賦形剤としては、浸透圧/等張調整剤、保存料、薬学的に許容され得る1種以上の緩衝剤及びpH調整剤、可溶化剤、ビヒクル、並びに、眼科組成物の処方に使用され得る、当技術分野にて慣習的な他の薬剤が挙げられる。
本発明の組成物は、本明細書に記載した処置方法での使用のために、眼科軟膏の形態で提供されてもよい。眼科軟膏は、概して、治療化合物と、水性媒体に溶解した比較的高い濃度の固体水溶性ポリマー(下記に記載する)とを含む、粘性かつ均質の混合物である。
本発明の組成物は、本明細書に記載した処置方法にて眼科インサートの形態で使用されるように提供され得る。インサートは、眼の盲管内に配置されて、本発明の組成物を長期間放出するよう適合された、無毒の固体水溶性ポリマー系の材料であり得る。
要約
目的:眼瞼炎に関連したドライアイの新規な治療法としての局所スタチンの研究。方法:ドライアイ及び眼瞼炎の症状及び徴候を有する10人の患者を、局所スタチン療法の前向きパイロット試験に1ヶ月間登録した。主な評価項目は、角膜フルオレセイン染色であった。結果:ベースラインから、4週目における試験の完了迄の、角膜フルオレセイン染色における≧3点の改善は、6〜10人の患者の試験眼内で見出された。主観的なドライアイ症状は改善した(p=0.005)。局所スタチンは、眼瞼炎スコア(p=0.011)及び涙膜破壊時間(p=0.005)を有意に改善した。重篤又は不可逆的な副作用は存在しなかった。結論:局所スタチンは、ドライアイ及び眼瞼炎を有する患者にとって好適な治療法である。局所スタチンは、容易に製造でき、広く入手可能であり得る。
眼瞼炎に関連したドライアイの症状及び徴候の軽減における局所スタチンの可能性の試験。
非比較パイロット試験を行って、局所スタチン療法の効力及び安全性を示し、また計画された前向き無作為対照試験を強化した。10人の患者を登録し、試験を完了した。
1)ドライアイ及び眼瞼炎の任意の症状
2)ドライアイの任意の症状:
BUT(涙液破壊時間)≦5秒、又は
少なくとも一方の眼内に点状上皮びらん
3)眼瞼炎の任意の症状:
瞼縁前部−グリース、皮膚鱗屑、捲縮輪、明かな潰瘍(frank ulcer)、睫毛損失及び炎症
瞼縁後部−チーズ状分泌物、遮断されたマイボーム腺>1/3、毛細血管拡張症、マイボーム腺炎、眼瞼縁切痕及び霰粒腫
を有する患者
4)年齢18歳以上の男性又は女性患者
5)書面によるインフォームド・コンセントを提供することができ、試験プロトコルに従う患者
1)過去6週間以内に実験薬物を受容した患者
2)4週間前迄に人工涙液以外の任意の局所処置を受けた患者
3)コンタクトレンズを着用している患者
4)能動的免疫学的融解(active immunological melt)−関節リウマチ、全身性エリテマトーデス、結節性多発動脈炎、顕微鏡的多発血管炎、ウェゲナー、モーレン潰瘍
6)活性細菌、真菌、又はアメーバ性感染性潰瘍
7)急性単純ヘルペスウイルス、帯状疱疹ウイルス、又は他の角膜炎若しくは炎症性結膜疾患
8)ビタミンA欠乏症
9)再発性角膜びらん症候群
10)妊娠又は授乳中の女性
アトルバスタチン(50マイクロM)を両眼に1滴、1日8回
効力評価:
1)主観的
症状スコアの合計
顔面スコア(Goto et al 2002)
2)客観的
a)涙膜破壊時間(BUT)
b)角膜フルオレセイン染色
b)眼瞼炎スコア
c)眼球結膜充血
d)局所療法の同時使用
1)BSCVA
2)白内障
3)IOP
4)有害反応
分析に先だって、完了した試験の形式上(proformas)の情報を、試験用に設計したMicrosoft Accessデータベースに入力した。効力変数に関しては、最悪の眼のデータのみを分析した。最悪の眼は、登録時に眼球症状、角膜フルオレセイン染色、及び眼瞼炎スコアの最大合計を有する眼として定義した。両眼が同一程度に発症していた場合、右眼を分析のために選択した。安全性解析の全部に両眼のデータを含めた。
ドライアイ及び眼瞼炎を有する7人の女性及び3人の男性患者の10個の眼が、パイロット試験に予め登録した。患者の平均年齢は70歳(53〜84歳の範囲)であった。全患者が試験を完了した(経過観察迄の損失なし、及び退薬なし)。原発性及び続発性シェーグレン症候群に関連したドライアイを有する患者は存在しなかった。緑内障を有する患者は存在せず、3人が試験眼内に以前の眼内手術を有した。
角膜フルオレセイン染色スコアは、試験眼内にて10人の患者のうち9人で2ポイント以上改善した(p=0.007)。試験のベースラインから4週目の試験完了までに、10人の患者のうち6人の試験眼内に、角膜フルオレセイン染色の改善が見られた。
涙膜時間(BUT)は、10人の患者全員で有意に改善した(p=0.005、表2)。8人の患者で眼瞼炎スコアが改善し、2人で変化が存在しなかった(P=0.011)。5人の患者で結膜充血が軽減し、5人は同一の状態のままであった(p=0.025)。Schirmer I試験結果には有意な変化が存在しなかった。
ベースラインから試験完了まで、安全性データは、BCVAに関して試験眼又は他方の眼にて有意な変化を示さず(表4)、白内障に罹る患者は存在しなかった。試験眼内でIOPの変化は存在しなかった。他方の眼内では、IOPは、10人の患者のうち8人にて試験完了時に、より低かった(p=0.035)。
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Claims (24)
- 眼表面炎症性疾患を有する個人における涙膜の安定化方法において、
不安定な涙膜により特徴付けられる眼表面炎症性疾患を有する個人を提供し、
前記個人の眼表面に化合物を提供して、マイバム産生組織によるコレステロールの合成を低減することによって、
前記個人の前記涙膜を安定化するステップを含むことを特徴とする、方法。 - 請求項1に記載の方法において、マイバム産生組織によるコレステロールの合成を低減する前記化合物が、HMG CoA還元酵素阻害剤であることを特徴とする方法。
- 請求項2に記載の方法において、前記HMG CoA還元酵素阻害剤がスタチンであることを特徴とする方法。
- 請求項3に記載の方法において、前記スタチンが、ヘキサヒドロナフタレン環を有することを特徴とする方法。
- 請求項4に記載の方法において、前記スタチンが、ロバスタチン、シンバスタチン又はプラバスタチンであることを特徴とする方法。
- 請求項3に記載の方法において、前記スタチンがフルオロフェニル環を有することを特徴とする方法。
- 請求項6に記載の方法において、前記スタチンが、フルバスタチン、アトルバスタチン、ロスバスタチン、プチバスタチン(ptiavastatin)、ダルバスタチン、グレンバシアチン(glenvasiatin)、ベルバスタチン、セルビバスタチン(cervivastatin)又はカルバスタチンであることを特徴とする方法。
- 請求項7に記載の方法において、前記化合物がアトルバスタチンであることを特徴とする方法。
- 請求項8に記載の方法において、アトルバスタチンが、50μMアトルバスタチン溶液から、1〜15滴/日の量で適用されることを特徴とする方法。
- 請求項9に記載の方法において、前記適用が1〜4週間であることを特徴とする方法。
- 請求項1に記載の方法において、マイバム産生組織によるコレステロールの合成を低減する前記化合物が、アンドロゲン又はホルモンであることを特徴とする方法。
- 請求項1乃至11の何れか一項に記載の方法において、抗炎症化合物及び/又は免疫抑制剤を前記個人の眼表面に提供するステップを含むことを特徴とする方法。
- 請求項12に記載の方法において、前記抗炎症化合物がステロイドであることを特徴とする方法。
- 請求項12に記載の方法において、前記免疫抑制剤がシクロスポリンであることを特徴とする方法。
- 請求項12乃至14の何れか一項に記載の方法において、マイバム産生組織によるコレステロールの合成を低減する前記化合物と、前記抗炎症化合物及び/又は免疫抑制剤とが、別個の投与単位にて提供されることを特徴とする方法。
- 請求項1乃至15の何れか一項に記載の方法において、前記個人の眼表面に抗生物質を提供するステップを含むことを特徴とする方法。
- 請求項16に記載の方法において、前記抗生物質が静菌剤又は殺菌剤であることを特徴とする方法。
- 請求項16又は17に記載の方法において、前記抗生物質が、ブドウ球菌(Staphylococcus)及び連鎖球菌(Streptococcus)種用の殺菌剤(bacteriocidal)であることを特徴とする方法。
- 請求項1乃至18の何れか一項に記載の方法において、前記疾患が後部眼瞼炎であることを特徴とする方法。
- マイバム産生組織によるコレステロールの合成を低減する化合物を含有する、眼科投与用に処方された組成物。
- 請求項20に記載の組成物において、前記化合物が、HMG CoA還元酵素阻害剤、アンドロゲン又はホルモンであることを特徴とする組成物。
- 請求項20又は21に記載の組成物において、抗炎症剤及び/又は免疫抑制剤を更に含有することを特徴とする組成物。
- 請求項22に記載の組成物において、前記抗炎症化合物がステロイドであることを特徴とする組成物。
- 請求項22に記載の組成物において、前記免疫抑制剤がシクロスポリンであることを特徴とする組成物。
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