JP5100025B2 - Retinal nerve cell protective agent containing prostaglandin F2α derivative as an active ingredient - Google Patents
Retinal nerve cell protective agent containing prostaglandin F2α derivative as an active ingredient Download PDFInfo
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- JP5100025B2 JP5100025B2 JP2006096393A JP2006096393A JP5100025B2 JP 5100025 B2 JP5100025 B2 JP 5100025B2 JP 2006096393 A JP2006096393 A JP 2006096393A JP 2006096393 A JP2006096393 A JP 2006096393A JP 5100025 B2 JP5100025 B2 JP 5100025B2
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- retinal
- cells
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- derivative
- prostaglandin
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Description
本発明はプロスタグランジンF2α誘導体を有効成分として含む網膜神経細胞保護剤に関する。 The present invention relates to a retinal nerve cell protective agent comprising a prostaglandin F2α derivative as an active ingredient.
網膜は内境界膜、神経線維層、神経節細胞層、内網状層、内顆粒層、外網状層、外顆粒層、外境界膜、視細胞層及び網膜色素上皮層の10層から成る、厚さ0.1〜0.5mmの組織であり、その中には視細胞、双極細胞、神経節細胞、水平細胞、アマクリン細胞及びミュラー細胞という網膜神経細胞群が存在する。 The retina consists of 10 layers: inner boundary membrane, nerve fiber layer, ganglion cell layer, inner reticular layer, inner granular layer, outer reticular layer, outer granular layer, outer boundary membrane, photoreceptor layer and retinal pigment epithelium layer The tissue has a thickness of 0.1 to 0.5 mm, and includes retinal nerve cell groups such as photoreceptor cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells, and Muller cells.
網膜神経細胞は光刺激を電気信号に変換して、脳へ伝達するといった視覚情報の受容と伝達において重要な役割を果たしている。 Retinal neurons play an important role in the reception and transmission of visual information, such as converting light stimuli into electrical signals and transmitting them to the brain.
その伝達メカニズムについて詳述すると、目から入った視覚情報は視細胞により電気信号化され、水平細胞、双極細胞及び/又はアマクリン細胞を経由した後に神経節細胞に伝達される。次いで、その電気信号は神経節細胞の軸策を含む視神経線維の束である視神経を経由して脳に伝達される。 When the transmission mechanism is described in detail, visual information entered from the eyes is converted into an electrical signal by the photoreceptor cell and transmitted to the ganglion cell after passing through the horizontal cell, the bipolar cell and / or the amacrine cell. The electrical signal is then transmitted to the brain via the optic nerve, which is a bundle of optic nerve fibers containing ganglion cell axons.
ところで、この網膜神経細胞が種々の原因により障害を受けると網膜神経細胞の恒常性(網膜血流循環による網膜神経細胞への酸素や栄養の供給といった機能等)が維持できなくなり視覚情報の脳への伝達が妨げられる。例えば、網膜血管閉塞症、糖尿病性網膜症、虚血性視神経症、緑内障、黄斑変性症、網膜色素変性症、レーベル病等の種々の網膜疾患おいて、網膜神経細胞の機能破綻が生じていることが広く知られている(非特許文献1)。 By the way, when this retinal nerve cell is damaged due to various causes, the homeostasis of the retinal nerve cell (functions such as supply of oxygen and nutrients to the retinal nerve cell by retinal blood circulation) cannot be maintained, and the visual information brain Transmission is hindered. For example, functional failure of retinal neurons has occurred in various retinal diseases such as retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, glaucoma, macular degeneration, retinitis pigmentosa, label disease, etc. Is widely known (Non-Patent Document 1).
最近、網膜神経細胞を障害する原因の一つとして、網膜虚血による網膜神経細胞死が考えられるようになり、この網膜虚血による網膜神経細胞死に関して、
1)網膜虚血による網膜神経細胞死の機序が脳虚血時の脳神経細胞死の機序に類似していること、
2)短期間の網膜虚血では網膜内層(内網状層)が選択的に傷害されること、
3)網膜虚血時にグルタミン酸の過剰遊離が確認できること、
4)グルタミン酸等の興奮性アミノ酸を硝子体内に注射することにより網膜神経細胞死が惹起すること、
5)網膜のN-メチル-D-アスパルテート(NMDA)受容体を介する過剰刺激が細胞内へのカルシウム(Ca)流入を促進し、その結果として一酸化窒素(NO)の誘導を介し細胞障害を惹起すること、等が報告されている(特許文献1、非特許文献2)。
Recently, retinal nerve cell death due to retinal ischemia has been considered as one of the causes of retinal nerve cell damage.
1) The mechanism of retinal neuronal cell death due to retinal ischemia is similar to that of cerebral neuronal cell death during cerebral ischemia.
2) In the short-term retinal ischemia, the inner layer of the retina (inner reticulated layer) is selectively damaged,
3) Confirmation of excessive release of glutamate during retinal ischemia,
4) Retinal nerve cell death is induced by injecting excitatory amino acids such as glutamate into the vitreous body.
5) Overstimulation via retinal N-methyl-D-aspartate (NMDA) receptor promotes calcium (Ca) influx into cells, resulting in cytotoxicity through induction of nitric oxide (NO) Has been reported (Patent Document 1, Non-Patent Document 2).
これらのことからグルタミン酸神経毒性抑制薬、NMDA受容体遮断薬、NO合成阻害薬等の薬物が網膜神経細胞障害に起因する眼疾患の治療に有用であると考えられ、現在、種々の検討がなされている。 Based on these findings, drugs such as glutamate neurotoxicity inhibitors, NMDA receptor blockers, and NO synthesis inhibitors are considered to be useful for the treatment of eye diseases caused by retinal neuronal cell damage. ing.
例えば、特許文献2にはβ遮断薬の一つであるニプラジロールを有効成分として含む網膜神経細胞保護剤が、特許文献3にはインターロイキン−1受容体アンタゴニストタンパクを有効成分として含む視神経節細胞保護剤が、特許文献4には塩酸ブリモニジン等のα1受容体遮断薬を有効成分として含む視神経節細胞保護剤が、非特許文献3にはプロスタグランジン誘導体の一つであるラタノプロストの神経保護作用等が開示されている。 For example, Patent Document 2 discloses a retinal nerve cell protective agent containing nipradilol, which is one of β-blockers, as an active ingredient, and Patent Document 3 discloses optic ganglion cell protection containing an interleukin-1 receptor antagonist protein as an active ingredient. Patent Document 4 discloses an optic ganglion cell protective agent containing an α 1 receptor blocker such as brimonidine hydrochloride as an active ingredient, and Non-patent Document 3 discloses a neuroprotective action of latanoprost, which is one of prostaglandin derivatives. Etc. are disclosed.
一方、プロスタグランジンF2α誘導体が特許文献5、特許文献6、特許文献7、特許文献8、特許文献9、特許文献10、特許文献11、特許文献12、特許文献13、特許文献14及び特許文献15に、眼圧下降作用を有する緑内障治療剤として開示されている。特許文献5には天然のプロスタグランジンF2α誘導体が、特許文献6にはラタノプロスト関連化合物が、特許文献7にはビマトプロスト関連化合物が、特許文献8にはトラボプロスト関連化合物が、特許文献9にはモノフルオロプロスタグランジンF2α誘導体が、特許文献10及び特許文献11にはジフルオロプロスタグランジンF2α誘導体が、また、特許文献12には多置換アリールオキシ基を有する含フッ素プロスタグランジンF2α誘導体が、特許文献13にはエーテル型ジフルオロプロスタグランジンF2α誘導体が、特許文献14にはジフルオロプロスタグランジンF2αアミド誘導体が開示されている。 On the other hand, prostaglandin F2α derivatives are disclosed in Patent Literature 5, Patent Literature 6, Patent Literature 7, Patent Literature 8, Patent Literature 9, Patent Literature 10, Patent Literature 11, Patent Literature 12, Patent Literature 13, Patent Literature 14, and Patent Literature. 15 discloses a therapeutic agent for glaucoma having an action of lowering intraocular pressure. Patent Document 5 discloses natural prostaglandin F2α derivatives, Patent Document 6 discloses latanoprost-related compounds, Patent Document 7 discloses bimatoprost-related compounds, Patent Document 8 discloses travoprost-related compounds, Patent Document 9 discloses Monofluoroprostaglandin F2α derivatives are disclosed in Patent Documents 10 and 11, difluoroprostaglandin F2α derivatives, and Patent Document 12 is a fluorine-containing prostaglandin F2α derivative having a polysubstituted aryloxy group. Reference 13 discloses an ether-type difluoroprostaglandin F2α derivative, and Patent Document 14 discloses a difluoroprostaglandin F2α amide derivative.
しかしながら、いずれの特許文献にも含フッ素プロスタグランジンF2α誘導体の網膜神経細胞保護作用については全く記載されていない。
プロスタグランジンF2α誘導体(特に含フッ素プロスタグランジンF2α)の新たな医薬用途を見出すことは非常に興味深い課題である。 Finding new pharmaceutical uses of prostaglandin F2α derivatives (especially fluorine-containing prostaglandin F2α) is a very interesting issue.
そこで、本発明者等はプロスタグランジンF2α誘導体の新たな医薬用途を見出すべく鋭意研究した結果、プロスタグランジンF2α誘導体がラット胎児網膜神経細胞において、濃度依存的にグルタミン酸誘発網膜神経細胞死を抑制すること、すなわち、プロスタグランジンF2α誘導体が網膜神経細胞に直接働き保護作用を示すこと、を見出し本発明を完成させた。 Thus, as a result of intensive studies to find a new medicinal use of the prostaglandin F2α derivative, the present inventors suppressed the glutamate-induced retinal neuronal cell death in a rat fetal retinal nerve cell in a concentration-dependent manner. That is, the present inventors have found that the prostaglandin F2α derivative directly acts on retinal neurons and exhibits a protective action, thereby completing the present invention.
本発明は、プロスタグランジンF2α誘導体を有効成分として含む網膜神経細胞保護剤に関する。 The present invention relates to a retinal nerve cell protective agent comprising a prostaglandin F2α derivative as an active ingredient.
本発明はまた、網膜神経細胞の保護方法、網膜神経細胞障害が関与する眼疾患の予防又は治療方法に関する。 The present invention also relates to a method for protecting retinal nerve cells and a method for preventing or treating eye diseases involving retinal nerve cell disorders.
本発明における「プロスタグランジンF2α誘導体」とは、プロスタン酸骨格から誘導されるプロスタグランジンF2α関連化合物を意味する。 The “prostaglandin F2α derivative” in the present invention means a prostaglandin F2α related compound derived from a prostanoic acid skeleton.
具体的には、特開平59−1418に開示されている天然のプロスタグランジンF2α誘導体、特表平3−501025に開示されているラタノプロスト関連化合物(但し、ラタノプロストを除く関連化合物又はその塩)、特表平8−501310に開示されているビマトプロスト関連化合物(好ましくはビマトプロスト又はその塩)、特開平10−182465に開示されているトラボプロスト関連化合物(好ましくはトラボプロスト又はその塩)、国際公開第98/12175号パンフレット、欧州特許出願公開第850926号明細書、特開2004−002462号公報、特開平10−259179号公報、特開2002−293771号公報、特開2003−321442号公報等に開示されている含フッ素プロスタグランジンF2α誘導体等のプロスタグランジンF2α誘導体又はその塩を有効成分として含む網膜神経細胞保護剤が挙げられる。 Specifically, a natural prostaglandin F2α derivative disclosed in JP-A-59-1418, a latanoprost-related compound disclosed in JP-A-3-501025 (however, a related compound excluding latanoprost or a salt thereof), Bimatoprost related compounds (preferably bimatoprost or a salt thereof) disclosed in JP-A-8-501310, travoprost related compounds (preferably travoprost or a salt thereof) disclosed in JP-A-10-182465, International Publication No. Disclosure in pamphlet No. 98/12175, European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002-293771, JP-A-2003-321442, etc. Fluorine-containing prostaglandin F2α Protective agent for a retinal neuronal cell containing a prostaglandin F2α derivative or a salt thereof of the conductor such as the active components.
好ましくは、「含フッ素プロスタグランジンF2α誘導体」を有効成分として含む網膜神経細胞保護剤が挙げられ、この「含フッ素プロスタグランジンF2α誘導体」とは、1又は複数個のフッ素原子を有するプロスタグランジンF2α誘導体を意味する。 Preferably, a retinal nerve cell protecting agent containing “fluorinated prostaglandin F2α derivative” as an active ingredient is mentioned, and this “fluorinated prostaglandin F2α derivative” is a prostagland having one or more fluorine atoms. A gin F2α derivative is meant.
具体的には国際公開第98/12175号パンフレット、欧州特許出願公開第850926号明細書、特開2004−002462号公報、特開平10−259179号公報、特開2002−293771号公報、特開2003−321442号公報等に開示されている含フッ素プロスタグランジンF2α誘導体を有効成分として含む網膜神経細胞保護剤が挙げられる。 Specifically, International Publication No. 98/12175, European Patent Application No. 850926, Japanese Patent Application Laid-Open No. 2004-002462, Japanese Patent Application Laid-Open No. 10-259179, Japanese Patent Application Laid-Open No. 2002-293771, Japanese Patent Application Laid-Open No. 2003-2003. And a retinal nerve cell protective agent containing a fluorine-containing prostaglandin F2α derivative disclosed in Japanese Patent No. -321422 as an active ingredient.
より好ましくは前記欧州特許出願公開第850926号明細書、特開2004−002462号公報、特開平10−259179号公報、特開2002−293771号公報及び特開2003−321442号等の公報中に記載されている15,15−ジフルオロプロスタグランジンF2α誘導体を有効成分として含む網膜神経細胞保護剤が挙げられる。 More preferably, it is described in the publications of the above-mentioned European Patent Application Publication No. 850926, Japanese Patent Application Laid-Open No. 2004-002462, Japanese Patent Application Laid-Open No. 10-259179, Japanese Patent Application Laid-Open No. 2002-293377, Japanese Patent Application Laid-Open No. 2003-321442, etc. And a retinal nerve cell protective agent containing a 15,15-difluoroprostaglandin F2α derivative as an active ingredient.
本発明は、下記一般式(1)で示される15,15−ジフルオロプロスタグランジンF2α誘導体又はその塩を有効成分として含む、視野異常、網膜血管閉塞症、糖尿病性網膜症、虚血性視神経症、黄斑変性症、網膜色素変性症および/またはレーベル病の予防又は治療のために使用する網膜神経細胞保護剤である。
[式中、Rはヒドロキシアルキル基、ホルミル基、カルボキシ基、アルコキシカルボニル基、アミノカルボニル基又はアルキルアミノカルボニル基を示す。以下同じ。]
ここで本明細書中で規定した各基又は文言について以下に示す。
[Wherein, R shows the hydroxyalkyl group, a formyl group, a carboxy group, an alkoxycarbonyl group, amino group or alkylamino group. same as below. ]
Here, each group or wording defined in this specification is shown below.
「ハロゲン」とはフッ素、塩素、臭素又はヨウ素を示す。 “Halogen” refers to fluorine, chlorine, bromine or iodine.
「アルキル」とは炭素原子数1〜6個の直鎖又は分枝のアルキルを示す。具体例としてメチル、エチル、n−プロピル、n−ブチル、n−ペンチル、n−ヘキシル、イソプロピル、イソブチル、sec−ブチル、tert−ブチル、イソペンチル等が挙げられる。 “Alkyl” refers to straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like.
「アルコキシ」とは炭素原子数1〜6個の直鎖又は分枝のアルコキシを示す。具体例としてメトキシ、エトキシ、n−プロポキシ、n−ブトキシ、n−ペンチルオキシ、n−ヘキシルオキシ、イソプロポキシ、イソブトキシ、sec−ブトキシ、tert−ブトキシ、イソペンチルオキシ等が挙げられる。 “Alkoxy” represents straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy and the like.
「アルキルアミノ」とは炭素原子数1〜12個のモノ又はジアルキルアミノを示す。具体的としてメチルアミノ、エチルアミノ、ジメチルアミノ、ジヘキシルアミノ等が挙げられる。 “Alkylamino” refers to mono- or dialkylamino having 1 to 12 carbon atoms. Specific examples include methylamino, ethylamino, dimethylamino, dihexylamino and the like.
さらに好ましい含フッ素プロスタグランジンF2α誘導体として、上記一般式(1)中、Rがカルボキシ基若しくはその塩基又はアルコキシカルボニル基を示す15,15−ジフルオロプロスタグランジンF2α誘導体が挙げられる。 More preferred fluorine-containing prostaglandin F2α derivatives include 15,15-difluoroprostaglandin F2α derivatives in which R in the general formula (1) represents a carboxy group, a base thereof, or an alkoxycarbonyl group.
特に好ましい含フッ素プロスタグランジンF2α誘導体として、上記一般式(1)中、Rがカルボキシ基若しくはその塩基又はイソプロポキシカルボニル基を示す15,15−ジフルオロプロスタグランジンF2α誘導体が挙げられる。 Particularly preferred fluorine-containing prostaglandin F2α derivatives include 15,15-difluoroprostaglandin F2α derivatives in which R in the general formula (1) represents a carboxy group, a base thereof, or an isopropoxycarbonyl group.
また、別の好ましい化合物として前記国際公開第98/12175号パンフレットに記載されている15−モノフルオロプロスタグランジンF2α誘導体が挙げられる。 Another preferred compound is the 15-monofluoroprostaglandin F2α derivative described in the pamphlet of WO 98/12175.
これらのプロスタグランジンF2α誘導体は塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸等の有機酸、リチウム、ナトリウム、カリウム等のアルカリ金属、カルシウム、マグネシウム等のアルカリ土類金属、アンモニア等と塩を形成することができ、これらの塩も本発明に含まれる。 These prostaglandin F2α derivatives are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, lithium A salt can be formed with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, ammonia and the like, and these salts are also included in the present invention.
本発明における「網膜神経細胞」とは視覚信号の脳への伝達に関与する神経細胞を意味する。具体的には視細胞、水平細胞、双極細胞、視神経節細胞、アマクリン細胞等を意味する。 The “retinal nerve cell” in the present invention means a nerve cell involved in transmission of a visual signal to the brain. Specifically, it means photoreceptor cells, horizontal cells, bipolar cells, optic ganglion cells, amacrine cells and the like.
本発明における「眼疾患」とは網膜神経細胞障害が関与する眼疾患を意味する。具体的には視野異常、網膜血管閉塞症、糖尿病性網膜症、虚血性視神経症、緑内障、黄斑変性症、網膜色素変性症、レーベル病等を意味し、好ましくは視野異常、網膜血管閉塞症、糖尿病性網膜症、虚血性視神経症、黄斑変性症、網膜色素変性症、レーベル病を意味する。 The “eye disease” in the present invention means an eye disease involving retinal nerve cell damage. Specifically, visual field abnormalities, retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, glaucoma, macular degeneration, retinitis pigmentosa, label disease etc., preferably visual field abnormalities, retinal vascular occlusion, It means diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, label disease.
本発明の網膜神経細胞保護剤は経口でも、非経口でも投与することができる。投与剤型としては点眼剤、眼軟膏、注射剤、錠剤、カプセル剤、顆粒剤、散剤等が挙げられ、特に点眼剤が好ましい。これらは汎用される技術、例えば特開平59−1418、特表平3−501025、特表平8−501310、特開平10−182465、国際公開第98/12175号パンフレット、欧州特許出願公開第850926号明細書、特開2004−002462号公報、特開平10−259179号公報、特開2002−293771号公報、特開2003−321442号公報、国際公開第02/22131号パンフレット等に開示されている技術を用いて製剤化することができる。 The retinal nerve cell protective agent of the present invention can be administered orally or parenterally. Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders, and the like, and eye drops are particularly preferable. These are general-purpose technologies, for example, JP-A-59-1418, JP-A-3-501025, JP-A-8-501310, JP-A-10-182465, International Publication No. 98/12175, and European Patent Application Publication No. 850926. Techniques disclosed in the specification, Japanese Patent Application Laid-Open No. 2004-002462, Japanese Patent Application Laid-Open No. 10-259179, Japanese Patent Application Laid-Open No. 2002-293377, Japanese Patent Application Laid-Open No. 2003-321442, pamphlet of International Publication No. 02/22131, etc. Can be formulated.
例えば、点眼剤は、塩化ナトリウム、濃グリセリン等の等張化剤、リン酸ナトリウム、酢酸ナトリウム等の緩衝化剤、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等を必要に応じて使用して、製剤化することができる。pHは眼科用製剤に許容される範囲内であれば特に問題はないが、pH4〜8の範囲が好ましい。
For example, eye drops include isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate,
眼軟膏は、白色ワセリン、流動パラフィン等の汎用される基剤を必要に応じて使用して、製剤化することができる。 The eye ointment can be formulated by using a widely used base such as white petrolatum, liquid paraffin or the like as necessary.
また、錠剤、カプセル剤、顆粒剤、散剤等の経口剤は、乳糖、結晶セルロース、デンプン、植物油等の増量剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ヒドロキシプロピルセルロース、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロース カルシウム、低置換ヒドロキシプロピルメチルセルロース等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂等のコーティング剤、ゼラチン皮膜等の皮膜剤等を必要に応じて使用して、製剤化することができる。 Oral preparations such as tablets, capsules, granules, powders, etc. are binding agents such as lactose, crystalline cellulose, starch, vegetable oil, etc., lubricants such as magnesium stearate, talc, hydroxypropylcellulose, polyvinylpyrrolidone, etc. Preparations using disintegrating agents such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and coating agents such as gelatin film as necessary. Can do.
投与量は症状、年令、剤型等により適宜選択できるが、点眼剤では0.00001〜1%(w/v)、好ましくは0.0001〜1%(w/v)のものを1日1〜数回点眼することができる。経口剤では通常1日当り0.01〜5000mg、好ましくは0.1〜1000mgのものを1〜数回に分けて投与することができる。 The dose can be appropriately selected depending on symptoms, age, dosage form, etc., but for eye drops, 0.00001 to 1% (w / v), preferably 0.0001 to 1% (w / v) per day Can be instilled one to several times. Oral preparations are usually administered in an amount of 0.01 to 5000 mg, preferably 0.1 to 1000 mg per day, in 1 to several divided doses.
後述の薬理試験の項で詳細に説明するが、ラット胎児網膜神経細胞を用いたグルタミン酸誘発網膜神経細胞死に対するプロスタグランジンF2α誘導体の効果を検討した。その結果、プロスタグランジンF2α誘導体は濃度依存的にグルタミン酸誘発網膜神経細胞死を抑制した。すなわち、プロスタグランジンF2α誘導体は網膜神経細胞保護作用を有しており、網膜神経細胞障害が関与する眼疾患の予防又は治療に有用である。 As will be described in detail in the section of the pharmacological test described later, the effect of the prostaglandin F2α derivative on glutamate-induced retinal neuronal cell death using rat fetal retinal neurons was examined. As a result, the prostaglandin F2α derivative suppressed glutamate-induced retinal neuronal cell death in a concentration-dependent manner. That is, the prostaglandin F2α derivative has a retinal nerve cell protective action and is useful for the prevention or treatment of eye diseases involving retinal nerve cell damage.
以下に本発明の製剤例及び薬理試験の結果を示す。尚、これらの例示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 The formulation example of this invention and the result of a pharmacological test are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.
[製剤例]
以下に本発明におけるプロスタグランジンF2α誘導体を含む一般的な製剤例を示す。
[Formulation example]
Examples of general preparations containing the prostaglandin F2α derivative in the present invention are shown below.
1)点眼剤 100ml中
プロスタグランジンF2α誘導体 10mg
濃グリセリン 2500mg
ポリソルベート80 2000mg
リン酸二水素ナトリウム二水和物 200mg
滅菌精製水 適量
1N塩酸又は1N水酸化ナトリウム 適量
pH 6.0
プロスタグランジンF2α誘導体及び添加物の種類ならびに量を適宜変更することにより所望の点眼剤を得ることができる。
1) Eye drops 10ml Prostaglandin F2α derivative 10mg
Concentrated glycerin 2500mg
Sodium dihydrogen phosphate dihydrate 200mg
Sterilized purified water appropriate amount 1N hydrochloric acid or 1N sodium hydroxide appropriate amount pH 6.0
Desired eye drops can be obtained by appropriately changing the type and amount of the prostaglandin F2α derivative and additives.
2)眼軟膏 100g中
プロスタグランジンF2α誘導体 0.1g
流動パラフィン 20g
白色ワセリン 77.9g
精製ラノリン 2g
プロスタグランジンF2α誘導体及び添加物の種類ならびに量を適宜変更することにより所望の眼軟膏を得ることができる。
2) Prostaglandin F2α derivative 0.1g in 100g of eye ointment
Liquid paraffin 20g
White petrolatum 77.9g
Purified lanolin 2g
A desired eye ointment can be obtained by appropriately changing the type and amount of the prostaglandin F2α derivative and additives.
[薬理試験]
プロスタグランジンF2α誘導体の新たな医薬用途を見出すために、ラット胎児網膜神経細胞を用いて、プロスタグランジンF2α誘導体のグルタミン酸誘発網膜神経細胞死に対する網膜神経細胞保護作用を評価検討した。
[Pharmacological test]
In order to find a new pharmaceutical use of prostaglandin F2α derivatives, rat fetal retinal neurons were used to evaluate and evaluate the protective effect of prostaglandin F2α derivatives against glutamate-induced retinal neuronal cell death.
尚、被験化合物であるプロスタグランジンF2α誘導体として16−フェノキシ−15−デオキシ−15,15−ジフルオロ−17,18,19,20−テトラノルプロスタグランジンF2αを使用した。 In addition, 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor prostaglandin F2α was used as a test compound prostaglandin F2α derivative.
(1)網膜神経細胞の単離培養
妊娠SDラットを全身麻酔下で開腹し、子宮をハンクス平衡塩溶液(Hanks’s Balanced Salt Solution、HBSS)の入ったシャーレ中に移した。子宮からラット胎児を摘出し、ラット胎児の眼球をとりだした。実体顕微鏡下でその眼球から網膜を摘出し、医科用メスで細かく刻んだ。さらに網膜を細胞レベルまで細かくし、ナイロンメッシュ(No.305 NBC工業(株)製)に通して細胞の塊を除き、透過物を1000 rpmで4 分間遠心した。上清を取り除き、残った細胞に適量の10 % 牛胎児血清(fetal bovine serum、FBS)含有改変イーグル培地(Modified Eagle’s Medium、MEM)を加えて懸濁させた。血球計算板で細胞数を数えた後、10%FBS含有MEM培地を加え、細胞数0.8×106cells/mlの細胞懸濁液を得た。細胞懸濁液を80 μlずつポリエチレンイミンコーティングプラスチックディスクに播種し、インキュベータ(37℃・5% CO2)に静置した。培地交換は細胞播種日を培養1日目とし、偶数日目に行った。尚、4日目までは10% FBS含有MEM培地を使用し、8日目以降は10%馬血清(Horse Serum、HS)含有MEM培地を使用した。ただし、6日目は増殖性細胞を除去するため、シタラビン(Ara-C)含有培地(1.5×10-5M in 10% FBS含有MEM培地)6 mlを使用した。
(1) Isolation and culture of retinal neurons Pregnant SD rats were opened under general anesthesia, and the uterus was transferred into a petri dish containing Hanks's Balanced Salt Solution (HBSS). The rat fetus was removed from the uterus and the eyeball of the rat fetus was removed. The retina was removed from the eyeball under a stereomicroscope and finely chopped with a scalpel. Further, the retina was made finer to the cell level, passed through a nylon mesh (No.305 NBC Kogyo Co., Ltd.) to remove cell clumps, and the permeate was centrifuged at 1000 rpm for 4 minutes. The supernatant was removed, and the remaining cells were suspended by adding a suitable amount of 10% fetal bovine serum (FBS) -containing modified Eagle's Medium (MEM). After counting the number of cells with a hemocytometer, MEM medium containing 10% FBS was added to obtain a cell suspension having a cell number of 0.8 × 10 6 cells / ml. 80 μl of the cell suspension was seeded on a polyethyleneimine-coated plastic disc and allowed to stand in an incubator (37 ° C., 5% CO 2 ). The medium was replaced on the even day, with the cell seeding day being the first day of culture. In addition, a 10% FBS-containing MEM medium was used until the 4th day, and a 10% horse serum (Horse Serum, HS) -containing MEM medium was used after the 8th day. However, on the 6th day, 6 ml of cytarabine (Ara-C) -containing medium (1.5 × 10 −5 M in 10% FBS-containing MEM medium) was used to remove proliferating cells.
(2)被験化合物含有HS含有MEM培地の調製
被験化合物2mgを100%エタノールに溶解し、HS含有MEM培地で順次希釈し、0.1nM、1nM、10nM及び100nMの被験化合物含有HS含有MEM培地を調製した。
(2) Preparation of test compound-containing HS-containing MEM medium 2 mg of test compound is dissolved in 100% ethanol and diluted sequentially with HS-containing MEM medium to prepare 0.1 nM, 1 nM, 10 nM and 100 nM test compound-containing HS-containing MEM medium did.
(3)被験化合物含有血清不含MEM培地の調製
被験化合物2mgを100%エタノールに溶解し、血清不含MEM培地で順次希釈し、0.1nM、1nM、10nM及び100nMの被験化合物含有血清不含MEM培地を調製した。
(3) Preparation of test compound-containing serum-free MEM medium 2 mg of test compound is dissolved in 100% ethanol, and diluted sequentially with serum-free MEM medium. 0.1nM, 1nM, 10nM, and 100nM test compound-containing serum-free MEM medium A medium was prepared.
(4)細胞死評価
培養10日目、細胞を播種・培養したプラスチックディスクを被験化合物含有HS含有MEM培地に移し24時間インキュベートした(37℃・5% CO2)。プラスチックディスクを1mMグルタミン酸含有血清不含MEM培地に移し10分間インキュベートした後、次いで被験化合物含有血清不含MEM培地に移し1時間インキュベートした(37℃・5% CO2)。細胞を1.5%トリパンブルー液で10分間染色した後、10%ホルマリン固定液を加えて細胞を固定した。生理食塩水で洗浄後、倒立型顕微鏡下で染色細胞及び非染色細胞を計数した。
(4) Cell death evaluation On the 10th day of culture, the plastic disc on which the cells were seeded and cultured was transferred to a test compound-containing HS-containing MEM medium and incubated for 24 hours (37 ° C., 5% CO 2 ). The plastic disc was transferred to 1 mM glutamic acid-containing serum-free MEM medium and incubated for 10 minutes, and then transferred to a test compound-containing serum-free MEM medium and incubated for 1 hour (37 ° C., 5% CO 2 ). The cells were stained with 1.5% trypan blue solution for 10 minutes, and 10% formalin fixative was added to fix the cells. After washing with physiological saline, stained cells and unstained cells were counted under an inverted microscope.
尚、前記被験化合物含有HS含有MEM培地の代わりにHS含有MEM培地を、被験化合物含有血清不含MEM培地の代わりに血清不含MEM培地を使用し、それ以外は前記と同様の試験を実施したものを基剤投与群とした。 In addition, HS-containing MEM medium was used instead of the test compound-containing HS-containing MEM medium, and serum-free MEM medium was used instead of the test compound-containing serum-free MEM medium. These were used as the base administration group.
また、前記被験化合物含有HS含有MEM培地の代わりにHS含有MEM培地を、被験化合物含有血清不含MEM培地の代わりに血清不含MEM培地を使用し、かつ、グルタミン酸含有血清不含MEM培地による処理を実施せず、それ以外は前記と同様の試験を実施したものを無処置群とした。 Further, using HS-containing MEM medium instead of the test compound-containing HS-containing MEM medium, using serum-free MEM medium instead of the test compound-containing serum-free MEM medium, and treatment with glutamic acid-containing serum-free MEM medium Otherwise, the same test as described above was carried out as an untreated group.
生存率を下記の計算式に基づき算出した。
(5)結果及び考察
図1に示したとおり、グルタミン酸処置により網膜神経細胞は、基剤添加群で約4割の細胞死が認められたが、培地として被験化合物含有HS含有MEM培地(0.1 nM〜100 nM)を使用したところ濃度依存的にグルタミン酸誘発網膜神経細胞死が抑制され、網膜神経細胞保護作用が確認された。
(5) Results and Discussion As shown in FIG. 1, about 40% of the retinal neurons were found to be dead in the group added with glutamate treatment, but the test compound-containing HS-containing MEM medium (0.1 nM) was used as the medium. When ˜100 nM) was used, glutamate-induced retinal neuronal cell death was suppressed in a concentration-dependent manner, and a protective effect on retinal neurons was confirmed.
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