JP2020523312A - 低用量ブリモニジンの組み合わせおよびその使用 - Google Patents
低用量ブリモニジンの組み合わせおよびその使用 Download PDFInfo
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- JP2020523312A JP2020523312A JP2019567535A JP2019567535A JP2020523312A JP 2020523312 A JP2020523312 A JP 2020523312A JP 2019567535 A JP2019567535 A JP 2019567535A JP 2019567535 A JP2019567535 A JP 2019567535A JP 2020523312 A JP2020523312 A JP 2020523312A
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- brimonidine
- glaucoma
- drug
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 230000007017 scission Effects 0.000 description 1
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- 230000036280 sedation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 229960000454 timolol hemihydrate Drugs 0.000 description 1
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- 229960001017 tolmetin Drugs 0.000 description 1
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Abstract
Description
緑内障薬との併用
約0.001%(w/v)のラタノプロストと、
約0,050%(w/v)のブリモニジンと、
約2.5%(w/v)のポリソルベートと、
約1.2%(w/v)のヒドロキシプロピルメチルセルロース(「HPMC」)と、
約5mMのホウ酸と、
任意に、約0.1%(w/v)ソルベートと、
を含む組成物であって、該組成物が約7.4のpHを有する、組成物を対象とする。
約0.05%(w/v)のチモロールと、
約0.050%(w/v)のブリモニジンと、
約2.5%(w/v)のポリソルベートと、
約1.2%(w/v)のHPMCと、
約4mMのホウ酸と、
任意に、約0.1%(w/v)のソルベートと、
を含む組成物であって、該組成物が、約7.4のpHを有する、組成物を対象とする。
ヒスタミンアンタゴニストとの併用
約0.0035%(w/v)のフマル酸ケトチフェンと、
約0.035%(w/v)のブリモニジンと、
約2.5%(w/v)のポリソルベートと、
約0.1%〜約1.2%(w/v)のHPMCと、
約4mMのクエン酸緩衝液と、
任意に、約0.1%(w/v)のソルベートと、
を含む組成物であって、該組成物が6.5のpHを有する、組成物を対象とする。
非ステロイド系抗炎症薬との併用
方法
正常圧の基線眼内圧(「IOP」、<21mmHg)を有する対象を、0.035%のブリモニジン、0.005%のラタノプロスト、および0.03%のブリモニジンと0,005%のラタノプロストとの併用、を含有する組成物の、単眼あたり1日2回点眼の単回投与で、5日間連続で予測的に処置した。1週間の休薬期を3回の処置周期の各々の間で観察した。投与は、午前8時30分に実施し、次いで1、3および5日後の投与と共に時間厳守で30秒の閉塞を実施した。
予備実験データに基づいて、検査される本発明の製剤は、ラタノプロスト単独よりも大きなIOP低減を予測的に達成した。さらに、ピークIOP低減効果は、投与後約4〜8時間で予測的に達成し、IOPは投与後24時間基線を下回ったままであった。図1は、0.005%のラタノプロストの投与後のIOP低減の予測的な例(0時間、白色の棒)対0.03%のブリモニジンと0.005%のラタノプロストの投与後のIOP低減(4、6、および8時間、黒色の棒)を実証している。実際、ELDBとラタノプロストとの併用投与後のIOPの低減は、投与前を除くすべての時間および日数で相乗作用を予測的に達成した。相乗作用は、IOPの低減を観察することと、IOPの予測された低減によって除して「相乗作用因子」を付与することによって計算されることになる。1よりも大きな相乗作用因子は、相乗作用を実証している。期待されるIOP低減は、次式を用いて計算されることになり、式中、AはELDB単独についてのIOP低減とし、Bはラタノプロスト単独についてのIOP低減とする。A+B−(AB/100)。したがって、本発明の製剤は、類似の検査条件下でブリモニジンおよびラタノプロスト単独での全濃度にわたる改善された性能を予測的に実証している。最後に、ラタノプロスト単独の間、対象は、ブリモニジンまたはブリモニジンとラタノプロストとの併用の検査の間には観察されなかった眼の充血を予測的に経験し、極めて低用量のブリモニジンが、IOP低減を亢進することができるだけでなく、緑内障薬の付随副作用を低減することもできることを実証した。
方法
鼻アレルギーに罹患している対象に、0.005%〜0.050%(w/v)のブリモニジンと0.025%〜0.035%(w/v)のフマル酸ケトチフェンまたは0.3%(w/v)のマレイン酸フェニラミンのいずれかとの併用を7日間連続で予測的に投与した。
検査した本発明の製剤は、ケトチフェンまたはフェニラミン単独よりもサイトカインおよび炎症における大きな低減を予測的に達成した。さらに、検査された本発明の製剤は、ケトチフェンおよびフェニラミンと関係した赤目を予測的に低減した。最後に、検査した本発明の製剤は、基線の白さを越えて、対象の眼を予測的にホワイトニングした。
Claims (36)
- 約0.01%〜約0.050%(w/v)のブリモニジンと有効量の第2の緑内障薬とを含む、緑内障の処置のための眼科用組成物であって、(w/v)が前記組成物の総体積による重量を示す、眼科用組成物。
- 前記ブリモニジンが、約0.035%〜約0.050%(w/v)の濃度である、請求項1に記載の組成物。
- 前記第2の緑内障薬が、プロスタグランジン、ベータ遮断薬、rhoキナーゼ阻害薬、および炭酸脱水酵素阻害薬からなる群から選択される、請求項1に記載の組成物。
- 前記緑内障薬が、ラタノプロスト、ビマトプロスト、トラバプロスト(travaprost)、タフルプロスト、ネタルスジル(netarsudil)、カルテオロール、チモプチク(timoptic)、チモロール、ベタロキソール(betaloxol)、レボブノロール、メチプラノロール、ブリンゾラミド、ドルゾラミド、アセタゾラミド、メタゾラミドおよびこれらの薬学的に許容される塩からなる群から選択される、請求項1に記載の組成物。
- 前記第2の緑内障薬が、約0.001%〜約1.0%(w/v)の濃度である、請求項1に記載の組成物。
- 前記第2の緑内障薬が、約0.001%〜約0.1%(w/v)の濃度のプロスタグランジン、または約0.01%〜約1.0%(w/v)の濃度のrhoキナーゼ阻害薬、または約0.1%〜約1.0%(w/v)の濃度のベータ遮断薬、または約0.5%〜約5%(w/v)の濃度の炭酸脱水酵素阻害薬である、請求項3に記載の組成物。
- 前記第2の緑内障薬が、約0.0015%〜約0.03%(w/v)の濃度のプロスタグランジン、約0.01%〜約0.05%(w/v)の濃度のrhoキナーゼ阻害薬、約0.25%〜約0.5%(w/v)の濃度のベータ遮断薬、または約1%〜約2%(w/v)の濃度の炭酸脱水酵素阻害薬である、請求項3に記載の組成物。
- ブリモニジンが約0.050%(w/v)の濃度であり、前記第2の緑内障薬が約0.005%(w/v)の濃度のラタノプロストである、請求項1に記載の組成物。
- ブリモニジンが約0.050%(w/v)の濃度であり、前記第2の緑内障薬が約0.05%(w/v)の濃度のビマトプロストである、請求項1に記載の組成物。
- ブリモニジンが約0.050%(w/v)の濃度であり、前記第2の緑内障薬が約0.5%(w/v)の濃度のチモロールである、請求項1に記載の組成物。
- ブリモニジンが約0.04%(w/v)の濃度であり、前記第2の緑内障薬が約2%(w/v)の濃度のドルゾラミドである、請求項1に記載の組成物。
- 非イオン性界面活性剤と、増粘剤と、緩衝液をさらに含み、ソルベートをさらに含んでもよい、請求項1に記載の組成物。
- 前記非イオン性界面活性剤が、約1%〜約5%(w/v)の濃度のポリソルベートである、請求項12に記載の組成物。
- 緑内障を治療することを必要とする対象へ、請求項1に記載の組成物を投与することを含む、緑内障を治療する方法。
- 発赤の低減をさらに提供する、請求項14に記載の方法。
- 眼のホワイトニングをさらに提供する、請求項14に記載の方法。
- 結膜膨潤の低減、充血低減、眼のホワイトニング、またはこれらの組み合わせをさらに提供する、請求項14に記載の方法。
- 約0.005%〜約0.050%のブリモニジンと有効量のヒスタミンアンタゴニストとを含む、アレルギーの治療のための眼科用組成物であって、(w/v)が前記組成物の総体積による重量を示す、眼科用組成物。
- 前記ブリモニジンが、約0.025%〜約0.035%(w/v)の濃度である、請求項18に記載の組成物。
- 前記ヒスタミンアンタゴニストが、ナファゾリン、アンタゾリン、アゼラスチン、カルビノキサミン、シプロヘプタジン、エメダスチン、ヒドロキシジン、レボカバスチン、ブロムフェニラミン、クロルフェニラミン、クレマスチン、ジフェンヒドラミン、ケトチフェン、ロラタジン、デスロラタジン、セチリジン、フェキソフェナジン、オロパタジン、アクリバスチン、エバスチン、ノルアステミゾール、レボセチリジン、ミゾラスチン、フェニラミン、これらの薬学的に許容される塩、およびそれらの組み合わせからなる群から選択される、請求項18に記載の組成物。
- 前記ヒスタミンアンタゴニストが、約0.025%〜約0.7%(w/v)の濃度である、請求項18に記載の組成物。
- 非イオン性界面活性剤と、ヒドロキシプロピルメチルセルロースと、緩衝液をさらに含み、ソルベートをさらに含んでもよい、請求項18に記載の組成物。
- 前記非イオン性界面活性剤が、約1%〜約5%(w/v)の濃度のポリソルベートである、請求項22に記載の組成物。
- アレルギー応答を治療するかまたは予防する必要のある対象へ、請求項16に記載の組成物を投与することを含む、アレルギー応答を治療するかまたは予防する方法。
- 眼のホワイトニングをさらに提供する、請求項24に記載の方法。
- 小血管の選択的血管収縮、毛細管後小静脈漏出の低減、サイトカイン、ロイコトリエン由来の炎症の低減、またはこれらの組み合わせをさらに提供する、請求項24に記載の方法。
- 約0.005%〜約0.050%(w/v)のブリモニジンと有効量の非ステロイド系抗炎症薬(NSAID)とを含む、炎症の低減のための眼科用組成物であって、(w/v)が前記組成物の総体積による重量を示す、眼科用組成物。
- 前記ブリモニジンが、約0.025%〜約0.035%(w/v)の濃度である、請求項27に記載の組成物。
- 前記NSAIDが、ケトロラック、アスピリン、セレコキシブ、ジフルニサール、エトドラク、イブプロフェン、インドメタシン、ケトプロフェン、ナブメトン、ナプロキセン、オキサプロジン、サルサラート、スリンダク、トルメチン、およびこれらの薬学的に許容される塩、ならびにそれらの組み合わせからなる群から選択される、請求項27に記載の組成物。
- 前記NSAIDがケトロラックである、請求項29に記載の組成物。
- 前記NSAIDが、約0.02%〜約0.50%(w/v)の濃度である、請求項27に記載の組成物。
- 非イオン性界面活性剤と、増粘剤と、緩衝液をさらに含み、ソルベートをさらに含んでもよい、請求項27に記載の組成物。
- 前記非イオン性界面活性剤が、約1%〜約5%(w/v)の濃度のポリソルベートである、請求項32に記載の組成物。
- 炎症を低減する必要のある対象へ、請求項25に記載の組成物を投与することを含む、炎症を低減する方法。
- 約0.001%(w/v)のラタノプロストまたは0.05%(w/v)のチモロールと、
約0.050%(w/v)のブリモニジンと、
約2.5%(w/v)のポリソルベートと、
約1.2%(w/v)のヒドロキシプロピルメチルセルロースと、
約5ミリモル濃度のホウ酸を含み、
約0.1%(w/v)のソルベートをさらに含んでもよい、緑内障の治療のための組成物であって、
前記組成物が、約7.4のpHを有する、組成物。 - 約0.0035%(w/v)のフマル酸ケトチフェンと、
約0.035%(w/v)のブリモニジンと、
約2.5%(w/v)のポリソルベートと、
約0.1%〜約1.2%(w/v)のヒドロキシプロピルメチルセルロースと、
約4ミリモル濃度のクエン酸緩衝液を含み、
約0.1%(w/v)のソルベートをさらに含んでもよい、アレルギー性結膜炎の治療のための組成物であって、
前記組成物が、約6.5のpHを有する、組成物。
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