JP2004537533A - Optic nerve cell protective agent - Google Patents
Optic nerve cell protective agent Download PDFInfo
- Publication number
- JP2004537533A JP2004537533A JP2003504956A JP2003504956A JP2004537533A JP 2004537533 A JP2004537533 A JP 2004537533A JP 2003504956 A JP2003504956 A JP 2003504956A JP 2003504956 A JP2003504956 A JP 2003504956A JP 2004537533 A JP2004537533 A JP 2004537533A
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- protective agent
- retinal
- optic nerve
- disease
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Abstract
本発明は、式
【化１】
で示されるスルファメート誘導体を有効成分として含有することを特徴とする視神経細胞保護剤及び該スルファメート誘導体を用いる視神経細胞の保護のための方法に関する。The present invention relates to a compound of the formula
And a method for protecting optic nerve cells using the sulfamate derivative.
Description
【技術分野】
【０００１】
本発明はトピラメートに代表される下記式
【０００２】
【化１】
で示されるスルファメート誘導体を有効成分として含有する視神経細胞保護剤及び該スルファメート誘導体を用いる視神経細胞の保護のための方法に関する。
【背景技術】
【０００４】
網膜は外部からの光を受容する機能を有しており、視機能に関して重要な役割を果たしている。網膜は、構造的には網膜色素上皮膚を始め、内網状層、神経節細胞層、神経線維層等１０層の層から成る、厚さ約０．１〜０．５ｍｍの組織である。内網状層には、アマクリン細胞という神経節細胞突起と対をなしてシナプスを形成する神経細胞が存在している。これは、光の照射開始時と終了時によく応答することから、光強度の検出器として働くと考えられている。神経節細胞層にはその細胞体が網膜のもっとも内側に存在する神経細胞が存在しており、運動視、周辺視、色覚、形態覚などに深く関与している。また、神経線維層には網膜中心動静脈の分枝である網膜血管が走行しており、視神経に酸素および栄養を供給する役割を担っている。
【０００５】
最近、緑内障において、網膜血流循環や視神経軸策輸送の障害により、最終的には神経節細胞死による神経線維の脱落が生じ、視野障害へと進行していくことから、神経節細胞死を予防あるいは最小限に抑える治療を行うことが究極的な緑内障治療につながるという、いわゆる「ニューロプロテクション」という考え方が確立されつつある（眼科，４０，２５１−２７３，１９９８）。実際、高眼圧虚血ラットにおいて網膜神経節細胞層や視神経乳頭の障害が観察されたこと（Ｇｒａｅｆｅｓｒｃｈ．Ｃｌｉｎ．Ｅｘｐ．Ｏｐｈｔｈａｌｍｏｌ．，２３４，４４５−４５１，１９９６）やメチルセルロース誘発高眼圧ウサギにおいて１０日間の高眼圧後、網膜神経節細胞密度の有意な減少とグリア細胞密度の有意な増加を認め、神経節細胞の脱落と細胞の大きさに相関を認めたこと（ＧｒａｅｆｅｓＡｒｃｈ．Ｃｌｉｎ．Ｅｘｐ．Ｏｐｈｔｈａｌｍｏｌ．，２３４，Ｓ２０９−Ｓ２１３，１９９６）が報告されている。
【０００６】
網膜血管が攣縮、血栓、動脈硬化等の要因により閉塞または狭窄すると網膜血流循環に障害が生じ、網膜や視神経への酸素ならびに栄養の供給が閉ざされる。網膜血流循環障害は、網膜疾患の中で特に重要な位置を占めている。網膜血流循環障害に伴う症状の代表的な例として、網膜静脈や網膜動脈が閉塞あるいは狭窄した網膜血管閉塞症、網膜剥離の一因である糖尿病性網膜症、視機能障害が出現する虚血性視神経症がある。さらに、この網膜血流循環障害により酸素や栄養の供給が不足し、網膜神経節細胞は死に至る。その他の網膜疾患である黄斑変性症、網膜色素変性症、レーベル病などにおいても、この神経節細胞死が発症に深く関与すると考えられている。
【０００７】
また、眼疾患における多様な病態に、プログラム化細胞死の一形態であるアポトーシスが関与することが解明されつつある。例えば、虚血−再灌流による網膜障害（Ｊ．Ｏｃｕｌ．Ｐｈａｒｍａｃｏｌ．Ｔｈｅｒ．，１１，２５３−２５９，１９９５）、網膜剥離（Ａｒｃ．Ｏｐｈｔｈａｌｍｏｌ．，１１３，８８０−８８６，１９９５）、網膜色素変性症（Ｐｒｏｃ．Ｎａｔｌ．Ａｃａｄ．Ｓｃｉ．ＵＳＡ，９１，９７４−９７８，１９９４、Ｉｎｖｅｓｔ．Ｏｐｈｔｈａｌｍｏｌ．Ｖｉｓ．Ｓｃｉ．，３５，２６９３−２６９９，１９９４）、網膜光障害（Ｉｎｖｅｓｔ．Ｏｐｈｔｈａｌｍｏｌ．Ｖｉｓ．Ｓｃｉ．，３７，７７５−７８２，１９９６）、緑内障（Ｉｎｖｅｓｔ．Ｏｐｈｔｈａｌｍｏｌ．Ｖｉｓ．Ｓｃｉ．，３６，７７４−７８６，１９９５、Ｅｘｐ．ＥｙｅＲｅｓ．，６１，３３−４４，１９９５）などにおいて、網膜神経節細胞にアポトーシスが生じることが報告されている。つまり、原因は多様であっても、結果として生じる視機能障害は、視覚情報ネットワークを構成している神経細胞のアポトーシスが原因となっている可能性が高い。
【０００８】
一方、トピラメートは下記式
【０００９】
【化２】
２，３：４，５−ビス−Ｏ−（１−メチルエチリデン）−β−Ｄ−フラクトピラノース スルファメート
で示される抗痙攣活性を有する化合物として知られており（例えば、特公平５−５８２４号公報）、てんかんの処置剤として有効であることが報告されている（日薬理誌，１１５，５３−５７，２０００、Ａｍ．Ｊ．Ｈｅａｌｔｈ−Ｓｙｓｔ Ｐｈａｒｍ．，５５，５５４−５６２，１９９８）。また、トピラメートは房水産生に関与する炭酸脱水素酵素の阻害作用を有しており、眼圧下降剤として緑内障の治療に役立つことも報告されている（特公平５−５８２４号公報）。
【００１１】
また、ＰＣＴ国際公開ＷＯ ００／６１１３８には、トピラメート及びその誘導体が、糖尿病性神経障害及び糖尿病性網膜症を含む慢性の神経変性障害の処置に有用であることが開示されている。
【００１２】
さらに、ＰＣＴ国際公開ＷＯ ９８／００１２４には、トピラメート及びその誘導体が、急性虚血性神経障害の処置に有用であることが開示されている。
【００１３】
しかしながら、炭酸脱水素酵素が関与しない、網膜血管閉塞症、虚血性視神経症、黄斑変性症、網膜色素変性症、レーベル病等に代表される網膜疾患や緑内障性神経障害などの眼疾患にトピラメートがどのような影響を与えるのかについて報告はなく、また、眼組織、特に網膜神経節細胞などの視神経細胞にトピラメートがどのような影響を及ぼすかについても知られていない。
【発明の開示】
【００１４】
本発明者らは、トピラメートの緑内障治療薬としての開発研究の過程で、意外にも、トピラメートに代表される前記式（Ｉ）のスルファメート誘導体が視神経細胞に直接作用して、網膜神経細胞のアポトーシスを抑制する効果があることに加えて、神経節細胞層中の細胞数の減少及び内網状層の菲薄化を抑制する効果にも優れていること、したがって、網膜神経細胞のアポトーシスによって生ずる種々の疾患、例えば、緑内障性視神経障害や、網膜血管閉塞病、虚血性視神経症、黄斑変性症、網膜色素変性症、レーベル病などの網膜疾患の予防又は治療に有用であることを発見し、本発明を完成するに至った。
【００１５】
かくして、本発明は、式
【００１６】
【化３】
で示されるスルファメート誘導体を有効成分として含有することを特徴とする視神経細胞保護剤を提供するものである。
【００１８】
本発明は、また、上記式（Ｉ）のスルファメート誘導体を患者に投与することを特徴とする患者の視神経細胞の保護のための方法を提供するものである。
【００１９】
式（Ｉ）のスルファメート誘導体には、光学異性体やジアステレオ異性体が存在するが、本発明の薬剤において有効成分として使用される式（Ｉ）のスルファメート誘導体には、これらの異性体やそれらの混合物も包含される。また、本発明で使用する式（Ｉ）のスルファメート誘導体は例えば水和物の形態であってもよい。式（Ｉ）のスルファメート誘導体の中で、前記式（ＩＩ）で示されるトピラメートが特に好適である。
【００２０】
本発明の薬剤によって保護される視神経細胞には、網膜神経節細胞、アマクリン細胞、双極細胞、水平細胞、視細胞などが包含されるが、本発明の薬剤は、中でも特に、網膜神経節細胞のアポトーシスに対して効果的に作用する。
【００２１】
本発明による式（Ｉ）のスルファメート誘導体の視神経細胞保護作用を、トピラメートを用いた以下の薬理試験により具体的に説明する。
【００２２】
［薬理試験］
トピラメートの視神経細胞保護作用を検討すべく、トピラメートについて、（１）グルタミン酸によって惹起したラット胎児培養網膜神経細胞死に対する作用および（２）ラット水圧負荷虚血誘発網膜障害に対する作用を以下の方法で試験した。
【００２３】
（１）グルタミン酸によって惹起したラット胎児培養網膜神経細胞死に対するトピラメートの作用
ラット胎児（１７〜１９日齢）より網膜細胞を摘出・単離し、ポリエチレンイミンコートされたプラスチックカバースリップ上で１０％ウシ胎児血清含有イーグル基礎培地中にて７日間培養した。８日目からは１０％馬血清含有イーグル基礎培地で培養した。培養６日目にシトシンアラビノシド（１０μＭ）を添加して非ニューロン性の細胞の増殖を抑制した。つぎに、血清不含イーグル基礎培地に、グルタミン酸（１ｍＭ）および各種濃度のトピラメート（１０ｎＭ〜１００μＭ）を添加した培地で細胞を１０分間インキュベート（３７℃、５％ＣＯ２・９５％ 空気）した。グルタミン酸およびトピラメートを含まない血清不含イーグル基礎培地に細胞を戻し、１時間インキュベート（３７℃、５％ＣＯ２・９５％空気）後、トリパンブルー除去法により毒性の判定を行った。すなわち、細胞を１０％中性ホルマリン溶液にて固定し生理食塩液で洗浄した後、トリパンブルー溶液を加えることにより細胞を染色し位相差顕微鏡下で細胞を計数した。その際、トリパンブルーにより染色される細胞を死細胞、非染色細胞を生存細胞とし、計数細胞総数（２００以上）に対する生細胞の比から培養細胞の生存率を求めた。１ｍＭのグルタミン酸を単独で添加した群、１ｍＭのグルタミン酸と各濃度のトピラメートを共に添加した群をそれぞれ「１ｍＭグルタミン酸単独添加群」、「１ｍＭグルタミン酸＋（各種濃度の）トピラメート添加群」とした。これらの結果を全く処理を施していない「未処置群」についての対応する計測値と比較した。実験結果を表１に示す。なお、表中の値は平均値である。
【００２４】
【表１】
（２）ラット水圧負荷虚血誘発網膜障害に対するトピラメートの作用
ラットを３％ハロタンで麻酔導入し、１％ハロタンで維持した（ハロタンは、酸素０．５Ｌ／分、突気１．５Ｌ／分で気化させる）。つぎに、アトロピン点眼液で右眼を散瞳させ、生理食塩液の点滴用容器を天井から吊るしたチューブを介して繋いだ３０Ｇの注射針を前房内に刺入することにより１３０ｍｍＨｇの水圧を負荷し、虚血を誘発させた。４５分後に注射針をはずし、網膜血流を再灌流させた。投与は、生理食塩液（溶媒）および溶媒に溶解（一部懸濁）させたトピラメート（２００ｍｇ／ｋｇ体重）をそれぞれラットの腹腔内に注入することにより行った。また、投与は、虚血負荷２時間前および虚血負荷直後のそれぞれ二回行った。投与７日後に眼球を摘出した後、２％パラホルムアルデヒド−２．５％グルタルアルデヒド中で一晩固定後、パラフィン包埋、薄切し、ヘマトキシリン−エオジン（ＨＥ）で染色した病理組織切片（３μｍ厚）を作製した。１眼につき視神経乳頭部が入るように６０μｍ間隔で８枚作製した切片から任意に３切片を選択し、選択した切片について、視神経乳頭から左右いずれかの１〜１．５ｍｍ間の網膜の写真撮影を行い、網膜における神経節細胞層（ＧＣＬ）中の細胞数および内網状層（ＩＰＬ）の厚さを計測した。溶媒を投与して虚血を行った群、溶媒に溶解させたトピラメートを投与して虚血を行った群をそれぞれ「溶媒投与群」、「トピラメート投与群」とした。これらの結果を全く処理を施していない「正常（未処置）群」についての対応する計測値と比較した。実験結果を表２に示す。なお、表中の値は平均値である。
【００２６】
【表２】
上記表１に示す結果によれば、トピラメートは培養網膜神経細胞死（アポトーシス）を濃度依存的に顕著に抑制する効果を有していることがわかる。また、上記表２に示す結果から明らかなように、トピラメートは神経節細胞中の細胞数の減少及び内網状層の菲薄化を抑制する効果に優れていることがわかる。
【００２８】
したがって、トピラメートに代表される前記式（Ｉ）のスルファメート誘導体は、網膜神経節細胞などの視神経細胞の保護剤として、例えば、網膜血管閉塞症、糖尿病網膜症、虚血性視神経症、黄斑変性症、網膜色素変性症、レーベル病等に代表される網膜疾患や緑内障性視神経障害などの眼疾患に対する予防又は治療剤として極めて有用である。
【００２９】
式（Ｉ）のスルファメート誘導体は、これら眼疾患の予防又は治療に使用する場合、患者（哺乳動物、殊にヒト）に対して経口的又は非経口的に投与することができ、必要に応じて、製薬学的に許容され得る添加剤と共に、投与に適した剤型に製剤化される。経口投与に適した剤型としては、例えば、錠剤、カプセル剤、顆粒剤、散剤などが挙げられ、また、非経口投与に適した剤型としては、例えば、注射剤、点眼剤、点鼻剤、坐薬などが挙げられ、これらは当該分野で汎用されている通常の技術を用いて製剤化することができる。
【００３０】
例えば、錠剤は、乳糖、ブドウ糖、Ｄ−マンニトール、無水リン酸水素カルシウム、デンプン、ショ糖等の賦形剤；カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、クロスポピドン、デンプン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース等の崩壊剤；ヒドロキシプロピルセルロース、エチルセルロース、アラビアゴム、デンプン、部分アルファー化デンプン、ポリビニルピロリドン、ポリビニルアルコール等の結合剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、含水二酸化ケイ素、硬化油等の滑沢剤；精製白糖、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ポリビニルピロリドン等のコーティング剤；クエン酸、アスパルテーム、アスコルビン酸、メントール等の矯味剤などを適宜選択して用い製剤化することができる。
【００３１】
また、注射剤は、滅菌精製水及び等張化のための塩化ナトリウムなどを用いて調製することができる。
【００３２】
さらに、点眼剤は、塩化ナトリウム、濃グリセリンなどの等張化剤；リン酸ナトリウム、酢酸ナトリウムなどの緩衝化剤；ポリオキシエチレンソルビタンモノオレート、ステアリン酸ポリオキシル４０、ポリオキシエチレン硬化ヒマシ油等の界面活性剤；クエン酸ナトリウム、エデト酸ナトリウム等の安定化剤；塩化ベンザルコニウム、パラベン等の防腐剤などから必要に応じて選択して用い、製剤化することができ、ｐＨは眼科製剤に許容される範囲内にあればよいが、通常４〜８の範囲内が好ましい。
【００３３】
式（Ｉ）のスルファメート誘導体、例えばトピラメートの投与量は、剤型、投与すべき患者の症状の軽重、年令、体重、医師の判断等に応じて適宜変えるこができるが、経口投与の場合、一般には、成人に対し１日あたり０．１〜２０００ｍｇを１回又は数回に分けて投与することができ、また、注射剤の場合、一般には、成人に対し１日あたり０．０１〜２００ｍｇを１回又は数回に分けて投与することができる。さらに、点眼剤の場合には、通常、０．１〜１０％（ｗ／ｖ）の有効成分濃度のものを１日１回又は数回点眼することができる。
【００３４】
次に製剤例を掲げて本発明の薬剤をさらに具体的に説明するが、本発明はこれら製剤例のみに限定されるものではない。
【製剤例】
【００３５】
製剤例１（錠剤）
【００３６】
製剤例２（注射剤）
【００３７】
製剤例３（点眼剤）
[0001]
The present invention relates to the following formula represented by topiramate
Embedded image
And a method for protecting optic nerve cells using the sulfamate derivative.
[Background Art]
[0004]
The retina has a function of receiving light from the outside, and plays an important role in visual function. The retina is a tissue having a thickness of about 0.1 to 0.5 mm, which is structurally composed of 10 layers such as an inner plexiform layer, a ganglion cell layer, and a nerve fiber layer, including the skin on the retinal pigment. In the inner plexiform layer, there are neurons that form synapses in pairs with ganglion cell processes called amacrine cells. Since this responds well at the start and end of light irradiation, it is considered to function as a light intensity detector. The ganglion cell layer contains nerve cells whose cell bodies are located inside the retina, and is deeply involved in motor vision, peripheral vision, color vision, morphology, and the like. In the nerve fiber layer, retinal blood vessels, which are branches of the central retinal artery and vein, run, and play a role of supplying oxygen and nutrition to the optic nerve.
[0005]
Recently, in glaucoma, dysfunction of retinal blood circulation and optic nerve axon transport ultimately results in loss of nerve fibers due to ganglion cell death, and progresses to visual field impairment. The concept of so-called "neuroprotection", in which prevention or minimization treatment leads to ultimate glaucoma treatment, is being established (Ophthalmology, 40, 251-273, 1998). In fact, damage to the retinal ganglion cell layer and the optic disc in ocular hypertensive ischemic rats was observed (Graefesrch. Clin. Exp. Ophthalmol., 234, 445-451, 1996), and in methylcellulose-induced hypertensive rabbits. After 10 days of intraocular pressure, a significant decrease in retinal ganglion cell density and a significant increase in glial cell density were observed, and a correlation was observed between ganglion cell shedding and cell size (Graeffes Arch. Clin. Exp.). Ophthalmol., 234, S209-S213, 1996).
[0006]
When a retinal blood vessel is occluded or narrowed due to factors such as spasm, thrombus, or arteriosclerosis, retinal blood circulation is impaired, and supply of oxygen and nutrients to the retina and the optic nerve is shut off. Disorders of retinal blood circulation occupy a particularly important position in retinal diseases. Representative examples of symptoms associated with impaired retinal blood circulation include retinal vascular occlusion in which retinal veins and retinal arteries are occluded or narrowed, diabetic retinopathy that contributes to retinal detachment, and ischemic in which visual impairment appears If you have optic neuropathy. Furthermore, the supply of oxygen and nutrients becomes insufficient due to the retinal blood circulation disorder, and retinal ganglion cells die. It is considered that this ganglion cell death is also deeply involved in the development of other retinal diseases such as macular degeneration, retinitis pigmentosa, and Leber's disease.
[0007]
In addition, it is being elucidated that apoptosis, which is a form of programmed cell death, is involved in various pathological conditions in eye diseases. For example, retinal damage due to ischemia-reperfusion (J. Ocul. Pharmacol. Ther., 11, 253-259, 1995), retinal detachment (Arc. Ophthalmol., 113, 880-886, 1995), retinitis pigmentosa (Proc. Natl. Acad. Sci. USA, 91, 974-978, 1994, Invest. Ophthalmol. Vis. Sci., 35, 2693-2699, 1994), retinal photopathy (Invest. Ophthalmol. Vis. Sci., 1994). 37, 775-782, 1996), glaucoma (Invest. Ophthalmol. Vis. Sci., 36, 774-786, 1995, Exp. Eye Res., 61, 33-44, 1995) and the like. It has been reported that may occur. In other words, even if the cause is various, the resulting visual impairment is likely to be caused by apoptosis of nerve cells constituting the visual information network.
[0008]
On the other hand, topiramate has the following formula:
Embedded image
It is known as a compound having an anticonvulsant activity represented by 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate (for example, JP-B-5-5824) ), And has been reported to be effective as a therapeutic agent for epilepsy (Nihon Pharmaceutical Journal, 115, 53-57, 2000, Am. J. Health-System Pharm., 55, 554-562, 1998). It has also been reported that topiramate has an inhibitory effect on carbonic anhydrase, which is involved in aqueous humor production, and is useful as an intraocular pressure lowering agent for the treatment of glaucoma (Japanese Patent Publication No. 5-5824).
[0011]
Also, PCT International Publication WO 00/61138 discloses that topiramate and its derivatives are useful for treating chronic neurodegenerative disorders, including diabetic neuropathy and diabetic retinopathy.
[0012]
Further, PCT International Publication WO 98/00124 discloses that topiramate and its derivatives are useful for treating acute ischemic neuropathy.
[0013]
However, topiramate is not used in ophthalmic diseases such as retinal vascular obstruction, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, and Leber's disease, which do not involve carbonic anhydrase. No effect has been reported, nor has it been known what effect topiramate has on eye tissues, particularly optic nerve cells such as retinal ganglion cells.
DISCLOSURE OF THE INVENTION
[0014]
The present inventors have surprisingly discovered that during the course of research and development of topiramate as a therapeutic agent for glaucoma, the sulfamate derivative of the formula (I) represented by topiramate directly acts on optic nerve cells, thereby causing apoptosis of retinal nerve cells. In addition to having the effect of suppressing the number of cells in the ganglion cell layer, it is also excellent in the effect of suppressing the thinning of the inner plexiform layer. The present invention has been found to be useful for the prevention or treatment of diseases such as glaucomatous optic neuropathy, retinal vascular obstruction, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, and Leber's disease. Was completed.
[0015]
Thus, the present invention provides a compound of the formula
Embedded image
An optic nerve cell protective agent comprising a sulfamate derivative represented by the formula (1) as an active ingredient.
[0018]
The present invention also provides a method for protecting optic nerve cells of a patient, which comprises administering the sulfamate derivative of the above formula (I) to the patient.
[0019]
The sulfamate derivative of the formula (I) includes optical isomers and diastereoisomers, and the sulfamate derivative of the formula (I) used as an active ingredient in the drug of the present invention includes these isomers and those isomers. Are also included. The sulfamate derivative of the formula (I) used in the present invention may be in the form of, for example, a hydrate. Among the sulfamate derivatives of the formula (I), topiramate of the above formula (II) is particularly preferred.
[0020]
The optic nerve cells protected by the agent of the present invention include retinal ganglion cells, amacrine cells, bipolar cells, horizontal cells, photoreceptors, and the like. Acts effectively on apoptosis.
[0021]
The optic nerve cell protective action of the sulfamate derivative of the formula (I) according to the present invention will be specifically described by the following pharmacological test using topiramate.
[0022]
[Pharmacological test]
To examine the protective effects of topiramate on optic nerve cells, topiramate was tested for (1) the effects on glutamate-induced fetal rat retinal nerve cell death induced by glutamate and (2) the effects on rat hydration-induced ischemia induced retinal damage in the following manner. did.
[0023]
(1) Effect of Topiramate on Rat Fetal Cultured Retinal Neuronal Cell Death Induced by Glutamate Retinal cells were isolated and isolated from rat fetuses (17-19 days old), and 10% bovine fetuses were placed on polyethylene imine-coated plastic coverslips. The cells were cultured in serum-containing Eagle's basal medium for 7 days. From day 8, the cells were cultured in Eagle's basal medium containing 10% horse serum. On the sixth day of culture, cytosine arabinoside (10 μM) was added to suppress the growth of non-neuronal cells. Then, the serum-free Eagle's basal medium, and glutamate (1 mM) and various concentrations of incubation topiramate (10NM～100myuM) cells for 10 minutes at medium supplemented with (37 ℃, 5% CO 2 · 95% air). Returning the cells to serum-free Eagle's basal medium without glutamate and topiramate, 1 hour (37 ℃, 5% CO 2 · 95% air) after the determination of toxicity were performed by trypan blue exclusion method. That is, the cells were fixed with a 10% neutral formalin solution, washed with a physiological saline, and then stained by adding a trypan blue solution, and the cells were counted under a phase-contrast microscope. At that time, the cells stained with trypan blue were regarded as dead cells, and the unstained cells were regarded as viable cells, and the viability of the cultured cells was determined from the ratio of viable cells to the total number of counted cells (200 or more). The group to which 1 mM glutamic acid was added alone and the group to which both 1 mM glutamic acid and topiramate of each concentration were added were referred to as a “1 mM glutamic acid alone addition group” and a “1 mM glutamic acid + (various concentration) topiramate addition group”, respectively. These results were compared to the corresponding measurements for the "untreated group" that had not been treated at all. Table 1 shows the experimental results. The values in the table are average values.
[0024]
[Table 1]
(2) Effect of Topiramate on Rat Hydraulic Pressure-Ischemic Induced Retinal Injury Rats were anesthetized with 3% halothane and maintained with 1% halothane. Vaporize). Next, the right eye was mydriasis with atropine ophthalmic solution, and a 30 G injection needle connected via a tube hung from a ceiling with a saline solution drip container was inserted into the anterior chamber to release a water pressure of 130 mmHg. Loading and induced ischemia. After 45 minutes, the injection needle was removed and the retinal blood flow was reperfused. The administration was performed by injecting a saline solution (solvent) and topiramate (200 mg / kg body weight) dissolved (partially suspended) in the solvent into the intraperitoneal cavity of each rat. The administration was performed twice, two hours before the ischemic load and immediately after the ischemic load. Seven days after administration, the eyes were enucleated, fixed in 2% paraformaldehyde-2.5% glutaraldehyde overnight, embedded in paraffin, sectioned, and stained with hematoxylin-eosin (HE). Thickness). Three slices were arbitrarily selected from eight slices prepared at intervals of 60 μm so that the optic papilla enters each eye, and a photograph of the selected section was taken of the retina between 1 and 1.5 mm on either side of the optic papilla. The number of cells in the ganglion cell layer (GCL) in the retina and the thickness of the inner plexiform layer (IPL) were measured. A group to which ischemia was administered by administering a solvent and a group to which ischemia was administered by administering topiramate dissolved in a solvent were respectively referred to as a “solvent administration group” and a “topiramate administration group”. These results were compared to the corresponding measurements for the "normal (untreated) group" that had not been treated at all. Table 2 shows the experimental results. The values in the table are average values.
[0026]
[Table 2]
According to the results shown in Table 1 above, it can be seen that topiramate has an effect of significantly suppressing the death (apoptosis) of cultured retinal nerve cells in a concentration-dependent manner. Further, as is clear from the results shown in Table 2, it can be seen that topiramate is excellent in the effect of suppressing the decrease in the number of cells in ganglion cells and the thinning of the inner plexiform layer.
[0028]
Accordingly, the sulfamate derivative of the formula (I) represented by topiramate is used as a protective agent for optic nerve cells such as retinal ganglion cells, for example, retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, It is extremely useful as a prophylactic or therapeutic agent for eye diseases such as retinal diseases such as retinitis pigmentosa and Leber's disease and glaucomatous optic neuropathy.
[0029]
When used for the prevention or treatment of these eye diseases, the sulfamate derivative of the formula (I) can be administered orally or parenterally to a patient (mammal, especially human), and if necessary, Together with pharmaceutically acceptable excipients into a dosage form suitable for administration. Dosage forms suitable for oral administration include, for example, tablets, capsules, granules, powders and the like, and dosage forms suitable for parenteral administration include, for example, injections, eye drops, nasal drops And suppositories, which can be formulated using ordinary techniques commonly used in the art.
[0030]
For example, tablets include excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospopidone, starch, partially pregelatinized starch. Disintegrators such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinylalcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide , Hardened oils and other lubricants; purified sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol Coating agents such as pyrrolidone; citric acid, aspartame, ascorbic acid, may be formulated using appropriately selected and flavoring agents such as menthol.
[0031]
Injectables can also be prepared using sterile purified water and sodium chloride for isotonicity.
[0032]
Further, eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil and the like. Surfactants; stabilizers such as sodium citrate and sodium edetate; selected and used as necessary from preservatives such as benzalkonium chloride and paraben, and can be formulated as needed. It may be within the allowable range, but usually within the range of 4 to 8.
[0033]
The dosage of the sulfamate derivative of the formula (I), for example, topiramate, can be appropriately changed according to the dosage form, the severity of the condition of the patient to be administered, age, weight, judgment of a physician and the like. In general, 0.1 to 2000 mg per day can be administered to an adult once or in several divided doses. In the case of an injection, generally 0.01 to 2000 mg per day per adult can be administered. 200 mg can be administered once or in several divided doses. Further, in the case of eye drops, usually, an active ingredient concentration of 0.1 to 10% (w / v) can be instilled once or several times a day.
[0034]
Next, the drug of the present invention will be described more specifically with reference to formulation examples, but the present invention is not limited to these formulation examples only.
[Formulation example]
[0035]
Formulation Example 1 (tablet)
[0036]
Formulation Example 2 (injection)
[0037]
Formulation Example 3 (eye drops)
Claims (20)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001183192A JP2004331502A (en) | 2001-06-18 | 2001-06-18 | Optical nerve cell protecting agent |
| PCT/JP2002/005935 WO2002102369A2 (en) | 2001-06-18 | 2002-06-14 | Agent for protection of retinal neurons |
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| Publication Number | Publication Date |
|---|---|
| JP2004537533A true JP2004537533A (en) | 2004-12-16 |
| JP4393863B2 JP4393863B2 (en) | 2010-01-06 |
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| JP2003504956A Expired - Lifetime JP4393863B2 (en) | 2001-06-18 | 2002-06-14 | Optic nerve cell protective agent |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013166802A (en) * | 2007-04-13 | 2013-08-29 | Southern Research Inst | Neovascularization inhibitor, and usage method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013166802A (en) * | 2007-04-13 | 2013-08-29 | Southern Research Inst | Neovascularization inhibitor, and usage method |
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