JP2021505554A - 眼の後部の疾患を治療するためのドベシル酸を含む眼科用局所組成物 - Google Patents
眼の後部の疾患を治療するためのドベシル酸を含む眼科用局所組成物 Download PDFInfo
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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Abstract
Description
−治療有効量のドベシル酸及び/又は薬学的に許容可能な塩、又は該酸若しくは塩のいずれかのエステルと、
−1つ又は複数の薬学的に許容可能な局所眼用賦形剤及び/又は担体であって、当該賦形剤及び/又は担体はpH調整剤を含む。
適切な量のCDO又はエタムシル酸塩を適切な容器に量り入れ、表1に示す蒸留水を加える。
方法
経口投与後及び眼の点眼後のバイオアベイラビリティを比較するため、ラット及びウサギの動物モデルにおいて、CDOの眼内分布を決定した。
体重がおよそ200gのSprague Dawley(SD)ラットにおいて、CDOを10mg/ml(実施例1の組成物2)、100mg/ml(実施例1の組成5)で局所点眼(10μl/眼)により投与するか、又は水溶液中(それぞれ、実施例1の組成物1、3及び4による)50mg/kg、200mg/kg、若しくは750mg/kgで強制経口投与した。投与後15分、60分、180分及び360分に動物を安楽死させ、血漿、ならびに強膜、角膜、網膜、硝子体液/水晶体及び視神経を含む眼組織を収集した。
HED(ラット/ヒト)=6.2
8.3×6.2=51.5mg/kgラット(ラット体重0.2kg)=10mg(ラット用量等量)
体重がおよそ1.8kgのニュージーランドホワイトウサギにおいて、CDOを10mg/ml(実施例1の組成2)、100mg/ml(実施例1の組成5)の局所点眼(33μl/眼)により投与するか、又は水溶液中25mg/kg(実施例1の組成物1による)で強制経口投与した。投与後15分、60分、180分及び360分に動物を安楽死させ、血漿、ならびに網膜/脈絡膜、及び視神経を含む眼組織を収集した。
HED(ウサギ/ヒト)=3.1
8.3×3.1=25.7mg/kgウサギ(ウサギ体重1.75kg)=45mg(ウサギ用量等量)
マトリクスの種類に応じて、CDOの生体分析を行った。血漿の場合、メタノールを使用してタンパク質を沈殿させた。組織の場合、サンプルを、ジルコニウムビーズ及び溶媒としてメタノール/水(1:1)(体積/体積)を使用して、Mini Bead Beaterで粉砕した。遠心分離後、サンプルをUPLC−MS/MSで分析した。
ラットにおけるCDOの眼内分布(局所眼投与vs経口投与)
方法
眼の後部への薬物の吸収を確認するため、エタミシル酸塩の眼内分布をラットで決定した。
実施例2に記載される通りである。
次の表4に実験結果を示す。
方法
定常状態の網膜におけるCDOレベルを評価するため、糖尿病ラットにおける28日間の反復投薬研究を行った。実施例1のCDO組成物2及び5を、28日間の局所点眼(10μl/眼)TIDによって投与した。29日目にCDOを1回点眼し、投与15分後に網膜を採取した。
実施例2に記載される通りである。
次の表5は、28日間の反復投薬研究後に測定し、29日目のCDOの単回投与後15分に測定したμg/gの網膜組織におけるCDOの濃度を示す。
方法
クエン酸緩衝液(pH4.5)中60mg/kg体重のストレプトゾトシン(STZ)の単回腹腔内注射により、SD雄ラットで糖尿病を誘発した。STZ投与の7日後に血糖値を測定し、250mg/dlのレベルを糖尿病誘発とみなす閾値とした。一旦高血糖が確認されれば、10mg/mlのCDOによる眼科治療(10μl/眼の局所点眼)を開始し、28日間1日3回(TID)継続した。ラットを無作為に3つの群に分けた:I.対照(非糖尿病)、II.治療なしの糖尿病ラット及びIII.CDO10mg/mlの糖尿病ラット。
静脈内注射直後にエバンスブルー(EB)が血清アルブミンに結合する能力に基づいて、EB染色によって網膜血管を観察した。したがって、29日目の安楽死の60分前に、エバンスブルー3%を1ml/kgで尾静脈から注射した。眼球をパラホルムアルデヒド4%で固定した。網膜を解剖した直後にスライドにマウントし、蛍光顕微鏡で観察した。
抗酸化能を、ホモジナイズした網膜中のグルタチオンジスルフィド(GSSG)又は酸化型グルタチオンの濃度を測定することによって評価した。組織を29日目に収集し、1mM EDTAを含むPBS pH6〜7でホモジナイズした。10000rpmで遠心分離した後、上清のアリコートを0.1%ギ酸で希釈し、UPLC−MS/MSで分析した。
市販のキットSV Total RNA Isolation System(Promega)を使用して各網膜からRNAを単離し、使用するまで−80℃で保存した。相対mRNAレベルは、MX3000(Stratagene)定量PCRシステムを使用して定量した。逆転写及びcDNA増幅を、遺伝子の標的特異的プライマーを用いたワンステップqRT−PCR SYBRグリーンPCRマスターミックスを使用して行った。サーモサイクラーのパラメーターは、50℃で15分を1サイクル;95℃で2分間、続いて95℃で30秒、55℃で30秒、及び68℃で30秒を40サイクル、最後に95℃で60秒、55℃で30秒、及び95℃で30秒を1サイクルであった。
β−アクチン:(フォワードプライマー、5’−GTCGTACCACTGGCATTGTG−3’(配列番号1);及びリバースプライマー、5’−CTCTCAGCTGTGGTGGTGAA−3’(配列番号:2))。
TNF−α:(フォワードプライマー、5’−ATCTACTCCAGGTCCTCTTC−3’(配列番号3);及びリバースプライマー、5’−GATGCGGCTGATGGTGTG−3’(配列番号:4))。
網膜血管分布:
網膜を蛍光顕微鏡によって評価した。糖尿病ラット(未治療群II)では、網膜血管分布が明らかに損なわれ、微小血管病変が観察され、糖尿病性網膜症の初期段階と一致している。毛細血管からの透過性の増加とならんで、明らかな網膜血管漏出が観察された。この糖尿病未治療群IIでは、重度でない血管新生プロセスが観察された。10mg/mlのCDOで治療した糖尿病ラット(群III)は、網膜がよく保存されており、血管損傷の形跡のない明確な血管を示した。網膜の全体的な外観は、非糖尿病対照群Iに近かった。
糖尿病ラットのホモジナイズした網膜(未治療群II及び未治療群III)とならんで、対照群Iにおいて決定されたGSSGの濃度を図1に示す。糖尿病ラット(未治療)のGSSGの網膜濃度は、対照群の網膜濃度よりも高かった)(P<0.05、Bonferroni補正を伴う一元配置分散分析)。それにもかかわらず、10mg/mlのCDOで治療した糖尿病ラットは、対照群と同じレベルのGSSGの濃度に戻すことができ(P<0.01群IIvs群III、Bonferroni補正を伴う一元配置分散分析)、ラット糖尿病性網膜症モデルにおけるCDOの抗酸化能を実証した。これらの結果は、標的組織におけるCDOの活性、及び高レベルの血糖によって引き起こされる酸化ストレスプロセスに関連する活性酸素種の生成の大幅な防止を裏付ける。
糖尿病ラット(非治療群II及び治療群III)とならんで対照群I(非糖尿病)の網膜におけるTNF−αmRNAの相対的発現を図2に示す。糖尿病群IIの網膜において、炎症性サイトカインTNF−αレベルの増加が観察された。10mg/mlのCDOによる治療は、TNF−αレベルを有意に減少させることができ(P<0.01 群IIvs群III、Bonferroni補正を伴う一元配置分散分析)、さらに、治療群の発現は対照群よりも有意に低く、このラット糖尿病性網膜症モデルにおけるCDOの抗炎症効果を実証している。
方法
HET−CAMは、眼結膜のアナログである漿尿膜の血管の変化を模倣するDraize Rabbit Eye Testの代替方法であり、試験物質の潜在的な刺激を判断するために使用できる。この方法は、鶏卵試験−漿尿膜(HET−CAM:Hen´s Egg Test−Chorioallantoic Membrane)試験法(ICCVAM−Recommended Test Method Protocol,NIH Publication No.10−7553−Published2010)に記載される方法に基づいている。
HET−CAM眼刺激アッセイを実施し、NaCl0.9%(陰性対照)、NaOH0.1%(陽性対照)、エタムシル酸塩(100mg/ml)、ドベシル酸カリウム(100mg/ml)、及びCDO(100mg/ml)の代表画像を図3に示す。アッセイした活性成分は、いかなる溶解、出血、又は凝固のプロセスも引き起こさなかったため、刺激性がないと特徴付けられた。ISは刺激スコアである。
方法
糖尿病SD系雄性ラットを、実施例1のCDO組成物2及び5で28日間、1日3回治療した(10μl/眼の局所点眼)。研究を通して眼の外観の臨床評価を行った。
治療したラットの眼の臨床評価では刺激症状は明らかにならず、アッセイした組成物の良好な忍容性を示している。
特許文献
−EP2875811
−EP2777699
非特許文献
−Awwad et al.,“Principles of Pharmacology in the Eye”,British Journal of Pharmacology−2017,vol no.174 Issue 23,pp.:4205−4223.
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−Cuevas et al.,“Intravitreal Dobesilate Injection for Macular Oedema Secondary to Branch Retinal Vein Occlusion”,MOJ Clin Med Case−2016,vol.no.4(1):00078.
−ICCVAM−Recommended Test Method Protocol,NIH Publication No.10−7553−Published 2010
−Gaudana et al,“Ocular drug delivery”,American Association of Pharmaceutical Sci.2010 Sep;12(3):348−360.doi:10.1208/s12248−010−9183−3.Epub 2010 May 1.
−Vadlapudi et al,“Ocular Drug Delivery”,Chapter 10,pp.:2019−263.
−Simo et al.,“Mechanisms of retinal neuroprotection of calcium dobesilate:therapeutic implications”Neural Regen Res−2017,vol.no.12(10),pp.:1620−1622.
−del Amo et al.,“Current and future ophthalmic drug delivery systems.A shift to the posterior segment”,Drug Discovery Today−2008,vol.no.13(3/4),pp.:135−143
−Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers U.S.Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research(CDER)July 2005 Pharmacology and Toxicology.
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Claims (25)
- 眼の後部の疾患の治療及び/又は予防に使用するためのドベシル酸及び/又は薬学的に許容可能な塩、又は該酸若しくは該塩のいずれかのエステルであって、前記治療が、0.01mg/日〜400mg/日の局所用量の前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの投与を含む、ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記薬学的に許容可能な塩が、ドベシル酸のアルカリ金属塩、アルカリ土類金属塩、ドベシル酸と式(II)のアミンとの塩、及びそれらの組み合わせから選択される、請求項1に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
式中、R1、R2及びR3は、独立して−(C1〜C8)−アルキルラジカル又はHから選択される。 - ドベシル酸のアルカリ金属塩、ドベシル酸のアルカリ土類金属塩、及びそれらの組み合わせから選択される薬学的に許容可能な塩である、請求項1〜2のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- ドベシル酸カルシウムのドベシル酸アルカリ土類金属塩である、請求項1〜3のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- ドベシル酸と式(II)のアミンとの塩であって、式中、R1とR2は等しく、エチルラジカルである、請求項1〜2のいずれかに記載の使用のための、ドベシル酸及び/又は薬学的に許容可能な塩、又は酸若しくは塩のいずれかのエステル。
- 前記眼の後部の疾患が網膜及び/又は脈絡膜の病態、硝子体液の病態、後強膜の病態、視神経の病態、及びそれらの組み合わせから選択される、請求項1〜5のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は酸若しくは塩のいずれかのエステル。
- 前記眼の後部の疾患が、網膜脈管障害、黄斑症、遺伝性眼底ジストロフィー、特発性脈絡網膜症、中心性漿液性網膜症、全身性脈絡膜ジストロフィー、及びそれらの組み合わせから選択される網膜の病態及び/又は脈絡膜の病態である、請求項1〜6のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸又は前記塩のいずれかのエステル。
- 前記網膜血管障害が、糖尿病性網膜症、糖尿病性乳頭症、非糖尿病性網膜症、眼虚血症候群、高血圧網膜症、サラセミア網膜症、コーツ症候群、イールズ症候群、放射線網膜症、日光網膜症、パーチャー網膜症、ポリープ状脈絡膜血管症(PCV)、網膜細動脈瘤、網膜毛細血管瘤、白血病性網膜症、網膜虚血、慢性網膜障害、及びそれらの組み合わせから選択される、請求項7に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記黄斑症が、加齢性黄斑変性症(ARMD)、出血性ARMD、網膜血管腫性増殖、ポリープ状脈絡膜血管症、蜂巣状脈絡膜変性(malattia leventinese)、全層黄斑円孔、網膜黄斑前膜、黄斑部毛細血管拡張症、セロファン黄斑症又は黄斑パッカー、近視黄斑症(myopia maculopathy)、網膜の静脈血栓後の滲出性黄斑症、急性黄斑視神経網膜症、黄斑嚢胞(macular cystoids)、黄斑浮腫、網膜血管様線条(retinal angioid streaks)、脈絡膜襞(choroidal folds)、低眼圧性黄斑症及びそれらの組み合わせから選択され、前記遺伝性眼底ジストロフィーが、網膜色素変性症;限定されないがアッシャー症候群、点状白斑網膜炎、レーバー先天性黒内障、錐体のジストロフィー、桿体ジストロフィー、ビエッティ結晶性角膜網膜ジストロフィー、若年性黄斑ジストロフィー、全てのタイプの黄斑ジストロフィー、シュタルガルト病又は黄色斑眼底を含む非定型網膜色素変性症、アッシャー症候群及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7に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記後眼部の疾患が、黄斑下及び硝子体の出血、星状硝子体症、硝子体剥離、飛蚊症(eye floaters)又は飛蚊症(myodesopsia)、遺伝性硝子体網膜症、スティックラー症候群又はワーグナー症候群、及びそれらの組み合わせからなる群から選択される硝子体液の病態である、請求項1〜6のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記眼の後部の疾患が、視神経萎縮、視神経炎、神経網膜炎、虚血性神経障害、遺伝性視神経障害、中毒性弱視又は栄養性視神経障害、高眼圧症、原発性緑内障、続発性緑内障、緑内障に伴う虹彩角膜内皮症候群、視神経乳頭ドルーゼン又は視神経円板ドルーゼン(head drusen or optic disc drusen)、視神経乳頭浮腫、及びそれらの組み合わせからなる群から選択される視神経の病態である、請求項1〜6のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸又は前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの局所用量が0.01mg/日〜300mg/日である、請求項1〜11のいずれかに記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸又は塩のエステルの局所用量が0.01mg/日〜100mg/日である、請求項12に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの局所用量が0.01mg/日〜50mg/日である、請求項13に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの局所用量が0.01mg/日〜25mg/日である、請求項14に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの局所用量が0.01mg/日〜18mg/日である、請求項15に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 前記ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは塩のエステルの局所用量が0.01mg/日〜13mg/日である、請求項16に記載の使用のためのドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステル。
- 治療有効量のドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステルを、1つ又は複数の薬学的に許容可能な局所賦形剤及び/又は担体と共に含む、眼の後部の疾患の治療及び/又は予防に使用するための局所眼用医薬組成物であって、前記治療が、0.01mg/日〜400mg/日の局所用量のドベシル酸及び/又はその薬学的に許容可能な塩、又はそれらのエステルの投与を含む、局所眼用医薬組成物。
- ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステルを、重量/体積パーセントで0.02%〜20%重量/体積で含む、請求項18に記載の使用のための局所眼用医薬組成物。
- 前記薬学的に許容可能な塩が、ドベシル酸のアルカリ金属塩、ドベシル酸のアルカリ土類金属塩、ドベシル酸と式(II)のアミンとの塩、及びそれらの組み合わせから選択される、請求項18〜19に記載の使用のための局所眼用医薬組成物。
式中、R1、R2及びR3は、独立して−(C1〜C8)−アルキルラジカル又はHから選択される。 - 前記薬学的に許容可能な塩が、ドベシル酸のアルカリ金属塩、ドベシル酸のアルカリ土類金属塩、及びそれらの組み合わせから選択される、請求項18〜20のいずれかに記載の使用のための局所眼用医薬組成物。
- 前記薬学的に許容可能な塩が、ドベシル酸カルシウムのドベシル酸アルカリ土類金属塩である、請求項18〜21のいずれか一項に記載の使用のための局所眼用医薬組成物。
- 前記ドベシル酸の薬学的に許容可能な塩が、ドベシル酸と式(II)のアミンとの塩であり、R1及びR2が等しく、エチルラジカルである、請求項18〜20のいずれかに記載の使用のための局所眼用医薬組成物。
- 点眼液の形態である、請求項18〜23のいずれかに記載の使用のための局所眼用医薬組成物。
- 局所眼用医薬組成物であって、治療有効量のドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステルを、1つ又は複数の薬学的に許容可能な局所の眼の賦形剤及び/又は担体と共に含み、前記組成物が、ドベシル酸及び/又は薬学的に許容可能な塩、又は前記酸若しくは前記塩のいずれかのエステルを2日間〜30日間放出するため製剤化されている、局所眼用医薬組成物。
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