JPH02262518A - Intraocular pressure-adjusting agent - Google Patents
Intraocular pressure-adjusting agentInfo
- Publication number
- JPH02262518A JPH02262518A JP1084325A JP8432589A JPH02262518A JP H02262518 A JPH02262518 A JP H02262518A JP 1084325 A JP1084325 A JP 1084325A JP 8432589 A JP8432589 A JP 8432589A JP H02262518 A JPH02262518 A JP H02262518A
- Authority
- JP
- Japan
- Prior art keywords
- urapidil
- intraocular pressure
- eye drops
- cyclodextrin
- eye
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 claims abstract description 48
- 229960001130 urapidil Drugs 0.000 claims abstract description 48
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000004410 intraocular pressure Effects 0.000 claims description 34
- 230000001105 regulatory effect Effects 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 14
- 230000003444 anaesthetic effect Effects 0.000 abstract description 3
- 239000003589 local anesthetic agent Substances 0.000 abstract description 3
- 210000001747 pupil Anatomy 0.000 abstract description 3
- 230000007794 irritation Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 230000008602 contraction Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000003889 eye drop Substances 0.000 description 41
- 229940012356 eye drops Drugs 0.000 description 39
- 241000283973 Oryctolagus cuniculus Species 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002504 physiological saline solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 208000010412 Glaucoma Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 239000007979 citrate buffer Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000001116 FEMA 4028 Substances 0.000 description 3
- 206010030043 Ocular hypertension Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 3
- 229960004853 betadex Drugs 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000004478 pupil constriction Effects 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000003732 agents acting on the eye Substances 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229940023490 ophthalmic product Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明はウラピジルを有効成分として含有する眼圧調整
剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an intraocular pressure regulating agent containing urapidil as an active ingredient.
［従来の技術および発明が解決しようとする課題］
ウラピジルは６− ｔ ［３−（４−（ｏ−メトキシフ
ェニル）−１−ピペラジニル〕プロピル］アミノ）１．
３−ジメチルウラシルで表わされ降圧剤とじて知られて
いる（特公昭４７−４６０７５号公報および特公昭５９
−３４４７号公報参照）。[Prior art and problems to be solved by the invention] Urapidil is 6-t[3-(4-(o-methoxyphenyl)-1-piperazinyl]propyl]amino)1.
It is expressed by 3-dimethyluracil and is known as an antihypertensive agent (Japanese Patent Publication No. 47-46075 and Japanese Patent Publication No. 59-1989).
(Refer to Publication No. 3447).
ウラピジルは微量で顕著な血圧降下作用を示すため、例
えば眼科領域等で非経口的な局所投与によっても有効で
あることが示唆されるが、水に難溶であり、液剤にする
ことが困難であるため緑内障に有効であることは従来知
られていなかった。Since urapidil exhibits a significant hypotensive effect even in minute doses, it is suggested that it may be effective by parenteral topical administration in the ophthalmology field, for example, but it is poorly soluble in water and difficult to form into a liquid formulation. Therefore, it was not previously known that it was effective for glaucoma.
緑内障は良く知られている如く眼圧が正常状態より上昇
することにより起こる視機能障害であり、そのまま放置
すると失明に至る重篤な疾患である。As is well known, glaucoma is a visual dysfunction caused by an increase in intraocular pressure above the normal state, and is a serious disease that can lead to blindness if left untreated.
そこで本発明者らは、かかる実状に鑑みウラピジルを有
効成分とする緑内障のごとき高眼圧症の治療薬を開発す
べく鋭意研究努力した結果、点眼薬として必要な刺激性
の非常に少ない顕著な眼圧下降効果を有する緑内障のご
とき高眼圧症の治療薬を開発し、これを提供するに至っ
た。In view of this situation, the present inventors have made intensive research efforts to develop a treatment for ocular hypertension such as glaucoma containing urapidil as an active ingredient. We have developed and provided a drug for treating ocular hypertension such as glaucoma that has a pressure-lowering effect.
すなわち、本発明の目的は緑内障のような高眼圧症に有
効な眼科用薬である眼圧調整剤を提供することにある。That is, an object of the present invention is to provide an intraocular pressure regulating agent that is an ophthalmic drug effective for treating ocular hypertension such as glaucoma.
［課題を解決するための手段］
本発明は、ウラピジルを有効成分とする眼圧調整剤に関
する。[Means for Solving the Problems] The present invention relates to an intraocular pressure regulating agent containing urapidil as an active ingredient.
本発明の眼圧調整剤は、水溶液の形態で用いられるのが
使用上最も苦痛、不便がないので好ましい。製剤形態は
、水溶液に限定されるものではなく、油性点眼剤、除放
性点眼剤または懸濁液の形態で用いられてもよく、さら
に使用の際に適当な溶剤を用いて用時溶解または懸濁さ
れうる結晶形態などであってもよい。The intraocular pressure regulating agent of the present invention is preferably used in the form of an aqueous solution because it is the least painful and inconvenient to use. The formulation form is not limited to an aqueous solution, but may be used in the form of oil-based eye drops, sustained-release eye drops, or a suspension. It may also be in a crystalline form that can be suspended.
本発明の眼圧調整剤１ ｍｌ中のウラピジルの含有量は
Ｏ’、 ００１〜４０ｍｇ、なかでも０．１〜２０ｍｇ
が好ましく、０，５〜ｌｏｍｇがとくに好ましい。また
、ウラピジルとα−シクロデキストリン、β −シクロ
デキストリンまたはγ −シクロデキストリンなどのシ
クロデキストリンまたはその誘導体のモル比が１＋０．
５〜３，０であることが安定化、可溶化、刺激緩和など
の点から好ましく、に０．８〜１．５がとくに好ましい
。The content of urapidil in 1 ml of the intraocular pressure regulating agent of the present invention is O', 001 to 40 mg, especially 0.1 to 20 mg.
is preferable, and 0.5 to lomg is particularly preferable. Further, the molar ratio of urapidil to cyclodextrin or its derivatives such as α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin is 1+0.
It is preferably from 5 to 3.0 from the viewpoint of stabilization, solubilization, alleviation of irritation, etc., and particularly preferably from 0.8 to 1.5.
投与量は、通常１日１〜３回の割合で点眼するのが持続
性、眼圧降下作用などの点から好ましい。なお、本発明
の眼圧調整剤は通常１〜２滴／回（３５〜７０μΩ／回
）程度の投与量で用いられる。From the viewpoint of sustainability and intraocular pressure lowering effect, it is preferable to administer the drug to the eye at a rate of 1 to 3 times a day. The intraocular pressure regulating agent of the present invention is usually used at a dosage of about 1 to 2 drops/time (35 to 70 μΩ/time).
シクロデキストリンの誘導体の例としてはメチル化β
−シクロデキストリンおよびヒドロキシプロピル化β−
シクロデキストリンなどがあげられる。Examples of cyclodextrin derivatives include methylated β
-Cyclodextrin and hydroxypropylated β-
Examples include cyclodextrin.
また、前記有効成分としてウラピジルを用いて水溶液形
態の点眼薬を調製するには、該ウラピジルを水、生理食
塩水、クエン酸緩衝液などの水性溶剤に溶解して点眼薬
を調製するのが最も簡便であるので好ましい。また、用
いる溶剤は非水性溶剤であってもよい。Furthermore, in order to prepare eye drops in the form of an aqueous solution using urapidil as the active ingredient, it is best to prepare the eye drops by dissolving the urapidil in an aqueous solvent such as water, physiological saline, or citrate buffer. This is preferred because it is simple. Moreover, the solvent used may be a non-aqueous solvent.
他の製剤形態にある本発明の点眼薬を調製するには、有
効成分としてウラピジルを用いて、通常の方法にしたが
って調製すればよい。The eye drops of the present invention in other formulations may be prepared using urapidil as the active ingredient according to a conventional method.
本発明の眼圧調整剤には、ウラピジルとシクロデキスト
リンまたはシクロデキストリンの誘導体のほかに、Ｎａ
ＯＨ，ＨＣＩ、酢酸などのｐＨ調整剤、塩化ナトリウム
、塩化カリウムなどの等張化剤、チメロサールなどの殺
菌剤、ポリオキシエチレン硬化ヒマシ浦などの界面活性
剤、エチレンジアミン四酢酸ナトリウム（ＥＤＴＡ）、
亜硫酸水素ナトリウムなどの安定化剤、ル化ベンザルコ
ニウム、バラオキシ安息香酸メチルなどの保存剤、フェ
ニルエチルアルコール、クロロブタノールなどの防腐剤
、メチルセルロース、コンドロイチン硫酸などの増粘剤
等を適宜配合してもよい。In addition to urapidil and cyclodextrin or a cyclodextrin derivative, the intraocular pressure regulating agent of the present invention contains Na
pH adjusters such as OH, HCI, and acetic acid, tonicity agents such as sodium chloride and potassium chloride, disinfectants such as thimerosal, surfactants such as polyoxyethylene hardened castor, sodium ethylenediaminetetraacetate (EDTA),
Stabilizers such as sodium bisulfite, preservatives such as benzalkonium fluoride and methyl hydroxybenzoate, preservatives such as phenylethyl alcohol and chlorobutanol, and thickeners such as methyl cellulose and chondroitin sulfate are appropriately blended. Good too.
本発明の眼圧調整剤は、刺激性が少なく、瞳孔収縮作用
、局所麻酔作用等の副作用も少ない。The intraocular pressure regulating agent of the present invention is less irritating and has fewer side effects such as pupil constriction and local anesthetic action.
［実施例］
つぎに実施例をあげて、本発明の眼圧調整剤（以下、点
眼薬という）をさらに詳細に説明するが本発明はかかる
実施例にのみ限定されるものではない。[Examples] Next, the intraocular pressure regulating agent (hereinafter referred to as eye drops) of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.
実施例１
ウラピジルをクエン酸緩衝ｍ （ｐＨ４，０）に溶解さ
せて、ウラピジルを０．５重量％、１重量％および２重
量％含有する点眼薬（第４表記載の点眼薬）を調整した
（以下それぞれ０．５％ウラピジル点眼薬、１％ウラピ
ジル点眼薬および２％ウラピジル点眼薬という）。Example 1 Eye drops containing 0.5% by weight, 1% by weight, and 2% by weight of urapidil (eyedrops listed in Table 4) were prepared by dissolving urapidil in citrate buffer m (pH 4,0). (Hereinafter referred to as 0.5% urapidil eye drops, 1% urapidil eye drops and 2% urapidil eye drops, respectively).
えられた各点眼薬をつぎの試験に供した。またコントロ
ールとしてクエン酸緩衝液（ｐｌ＋４．０）を用いた。Each of the obtained eye drops was subjected to the following test. In addition, citrate buffer (pl+4.0) was used as a control.
試験例１（ウラピジルの正常成熟白色家兎への眼圧に対
する効果）
以下に示す方法により、ウラピジルの正常成熟白色家兎
への眼圧に対する効果を調べた。Test Example 1 (Effect of urapidil on intraocular pressure in normal adult white rabbits) The effect of urapidil on intraocular pressure in normal adult white rabbits was investigated by the method shown below.
（１）実験動物
体重２．５〜３．５ｋｇの正常成熟白色家兎（日本白色
在来種、６〜１３力月齢、以下、白兎という）の雄を４
羽ずつ計１６羽１群８眼用いた。(1) Experimental animals Four normal mature white domestic rabbits (Japanese white native breed, 6-13 months old, hereinafter referred to as white rabbits) weighing 2.5-3.5 kg were
A total of 16 birds each with 8 eyes per group were used.
＋２） Ａ１１ｌ定装置
眼圧測定には、アルコン（Ａｌｃｏｎ）社製空気眼圧計
にューマトノグラフ
（Ｐｎｃｕｍａｔｏｎｏｇｒａｐｈ” ） 、以下ＰＴ
Ｇという）を使用し、測定毎にキャリブレーションを行
ない、計ｆｌｌｌＪは３０分毎に同一人物が同一時刻に
行なった。+2) A11 constant device For intraocular pressure measurement, a pneumatic tonometer manufactured by Alcon and a pneumatonograph (hereinafter referred to as PT) were used.
G), and calibration was performed for each measurement, with a total of 30 minutes being carried out by the same person at the same time.
（３）使用薬剤の投与方法
試験に供する ０．５％、１９６および２％ウラピジル
点眼薬を点眼するに際してはマイクロピペットを用いて
５０μｇを正確に計り取り、それぞれ白兎４羽８眼に点
眼した。なお、対照群である家兎４羽８眼にはクエン酸
緩衝液（ｐＨ４，０）のみを供、誠意眼薬と同様にして
点眼した。(3) Method of administering the drugs used When applying the 0.5%, 196 and 2% urapidil eye drops to the eyes, 50 μg was accurately measured using a micropipette and each was instilled into 8 eyes of 4 white rabbits. In addition, citrate buffer (pH 4,0) alone was provided to 8 eyes of 4 domestic rabbits as a control group, and the eye drops were applied in the same manner as the sincerity eye drops.
（４）実験方法
眼圧計測は、白兎（４羽）を０．４％塩塩酸オキシブブ
ロイイン眼液で点眼局所麻酔したのち、ＰＴＣでまず両
眼の眼圧測定を行った。次いで各点眼薬の点眼後、３０
分間隔で１２０分まで両眼の眼圧をそれぞれ２回ずつ；
ｌ−１定し、点眼前との差を求めた。(4) Experimental method To measure the intraocular pressure, white rabbits (4 birds) were locally anesthetized with 0.4% oxybubroin hydrochloride eye solution, and then the intraocular pressure of both eyes was first measured using PTC. Then after instillation of each eye drop, 30
Check the intraocular pressure in each eye twice for up to 120 minutes at minute intervals;
l-1 was determined, and the difference from before the instillation was determined.
（５）測定結果
第１図に示されるごと＜、２％および１％ウラピジル点
眼薬は対照群に比し、有意な眼圧の低下を示した。点眼
３０分後の眼圧降下量は２％ウラピジル点眼薬では３．
１± ０．１２ ■ｏｇ、 １％ウラピジル点眼薬では
１．５士 ０．１４ ｌｌ１ｍ１１ｇであった。(5) Measurement Results As shown in Figure 1, the 2% and 1% urapidil eye drops showed a significant decrease in intraocular pressure compared to the control group. The amount of intraocular pressure reduction after 30 minutes of instillation was 3.3% for 2% urapidil eye drops.
For 1% urapidil eye drops, it was 1.5 ± 0.14 ml/ml.
し、かじ、０．５％ウラピジル点眼薬では眼圧低下の傾
向は認められるが有意ではなかった。However, with 0.5% urapidil eye drops, a tendency to lower intraocular pressure was observed, but it was not significant.
第１図は、点眼後の時間と眼圧の変化量との関係を示す
グラフである。なお、第１図中の各点は４羽の白兎の平
均値である。FIG. 1 is a graph showing the relationship between the time after instillation and the amount of change in intraocular pressure. In addition, each point in FIG. 1 is the average value of four white rabbits.
実施例２
ウラピジルを生理食塩水（β −シクロデキストリンを
含存する）に溶解させて、ウラピジルを ０．１重回％
、 ０．０１重量％、 ０．００１重量％およびｏ、ｏ
ｏｏｉ重量％含有する点眼薬（第６表記載の点眼薬、各
々の点眼薬のウラピジルとβシクロデキストリンのモル
比は１：１）をそれぞれ調整した（以下、それぞれ０．
１％ウラピジル点眼薬、Ｏ０吋％ウラピジル点眼薬、ａ
、ｏｏｔ％ウラピジル点眼薬およびｏ、ｏｏｏｉ％ウラ
ピジル点眼薬という）。Example 2 Urapidil was dissolved in physiological saline (containing β-cyclodextrin), and urapidil was dissolved at 0.1% by weight.
, 0.01% by weight, 0.001% by weight and o, o
Eye drops (eye drops listed in Table 6, the molar ratio of urapidil and β-cyclodextrin in each eye drop is 1:1) containing 0.
1% urapidil eye drops, O0% urapidil eye drops, a
, oot% urapidil eye drops and o,oooi% urapidil eye drops).
えられた各点眼薬をっぎの試験に供した。Each of the obtained eye drops was subjected to the following test.
試験例２（水負荷モデルに対するウラピジル点眼薬の効
果）
（１）実験動物
体重２．５〜３．５ｋｇの白兎（６〜１３力月齢）の雄
を６羽ずつ計３０羽１群１２眼用いた。Test Example 2 (Effect of Urapidil Eye Drops on Water Load Model) (1) Experimental Animals Six male white rabbits (age 6 to 13 months) weighing 2.5 to 3.5 kg, 30 in total, 12 eyes per group. there was.
（２）測定装置
眼圧ＩＩ定には、アルコン社製ＰＴＧを使用し、測定毎
にキャリブレーションを行ない、計測は３０分毎に同一
人物が同一時刻に行なった。(2) Measuring device A PTG manufactured by Alcon was used to determine the intraocular pressure II. Calibration was performed for each measurement, and measurements were performed by the same person at the same time every 30 minutes.
（３）水負荷
温水（約３７℃） ２００ｍ１を白兎３０羽に経口投
与して水負荷を行なった。(3) Water loading 200ml of warm water (approximately 37°C) was orally administered to 30 white rabbits for water loading.
（４）使用薬剤の投与方法
試験に供する ０．１％、０，０１％、０．００１％お
よび０．０００１％ウラピジル点眼薬を点眼するに際し
てはマイクロピペットを用いて５０μｇを正確に計り取
り、それぞれ白兎６羽１２眼に点眼した。点眼後３０分
後に上記方法で水負荷を行った。(4) Administration method of the drug used When applying 0.1%, 0.01%, 0.001% and 0.0001% urapidil eye drops to the eyes, accurately measure out 50 μg using a micropipette. The drops were applied to 12 eyes of 6 white rabbits. Thirty minutes after instillation, water loading was performed using the above method.
なお、対照群である白兎６羽１２眼には生理食塩水のみ
を供試点眼薬と同様にして点眼した。In addition, only physiological saline was instilled into 12 eyes of 6 white rabbits as a control group in the same manner as the test eye drops.
（５実験方法
眼圧計測は、白兎（６羽）を０．４％塩酸オキシブプロ
力イン点眼液で点眼局所麻酔したのち、ＰＴＧでまず両
眼の眼圧を測定した。次いで点眼後３０分に水負荷を行
ない以後３０分間隔で１２０分まで両眼の眼圧をそれぞ
れ２回ずつ測定し、水負荷前との差を求めた。(5 Experimental Methods To measure intraocular pressure, white rabbits (6 birds) were locally anesthetized with 0.4% oxybuproin hydrochloride ophthalmic solution, and then the intraocular pressure in both eyes was measured using PTG. Then, 30 minutes after the instillation. After water loading, the intraocular pressure of both eyes was measured twice at 30 minute intervals for up to 120 minutes, and the difference from before the water loading was determined.
（６）測定結果
第２図に示されるごと＜ｏ、１％、 ｏ、ｏｉ％、ｏ、
ｏｏｉ％、０．０００１％ウラピジル点眼薬は対照群に
比し有意な眼圧下降効果が認められた。(6) Measurement results as shown in Figure 2<o, 1%, o, oi%, o,
ooi%, 0.0001% urapidil eye drops had a significant intraocular pressure lowering effect compared to the control group.
第２図は水負荷後の時間と眼圧の変化量との関係を示す
グラフである。なお、第２図中の各点は６羽の白兎の平
均値である。FIG. 2 is a graph showing the relationship between the time after water loading and the amount of change in intraocular pressure. Note that each point in Figure 2 is the average value of six white rabbits.
試験例３（局所安全性） 以下の方法で眼局所安全性を検討した。Test example 3 (local safety) Local ocular safety was investigated using the following method.
く実験項目〉
■瞬目反応
体重２．８〜３．２ｋｇの白兎（８〜１２力月齢）の雄
を５羽ずつ計１０羽１群５眼を用い、それぞれの白兎５
羽の片眼に生理食塩水、実施例２でえられた０、１％ウ
ラピジル点眼薬をマイクロピペットを用いて５０μｇ正
確に計り取り点眼し、点眼前後５分間の瞬目を計数した
。Experimental Items> ■Blink reaction Using 5 male white rabbits (8 to 12 months old) weighing 2.8 to 3.2 kg in total, 10 birds each with 5 eyes in each group.
Accurately measured 50 μg of the 0.1% urapidil eye drops obtained in Example 2 and physiological saline using a micropipette was instilled into one eye of the wing, and the blinks were counted for 5 minutes before and after instillation.
結果を第１表に示す。The results are shown in Table 1.
■瞳孔径の経時変化
体重２．８〜３．２ｋｇの白兎（８〜１２力月齢）の雄
を５羽ずつ計ｌＯ羽１群５眼を用い、それぞれの白兎５
羽の片眼に生理食塩水、実施例２でえられた０、１％ウ
ラピジル点眼薬をマイクロピペットを用いて５０μｇ正
確に計り取り点眼し、点眼前および点眼後３０分、６０
分、１２０分および３６０分経過後の瞳孔径を測定した
。■Change in pupil diameter over time Using 5 male white rabbits (8 to 12 months old) weighing 2.8 to 3.2 kg, each with 5 eyes per group of 10 birds.
Physiological saline was added to one eye of the wing, and 50 μg of the 0.1% urapidil eye drops obtained in Example 2 was weighed and instilled into the eye using a micropipette, and the eyes were instilled for 30 minutes and 60 minutes before and after instillation.
The pupil diameter was measured after 120 minutes, 120 minutes, and 360 minutes.
結果を第２表に示す。The results are shown in Table 2.
■角膜反射
体重２．８〜３．２ｋｇの白兎（８〜１２力月齢）の雄
を５羽ずつ計１０羽１群５眼を用い、それぞれの白兎５
羽の片眼に生理食塩水、実施例２でえられた０、１％ウ
ラピジル点眼薬をマイクロピペットを用いて５０μｇ正
確に計り取り点眼し、点眼前および点眼後５分間隔で３
０分間角膜表面を丸めたキムワイブ（十條キンバリー■
製）で５回刺激して反射回数を計数した。■ Corneal reflection Using 5 male white rabbits (8 to 12 months old) with a weight of 2.8 to 3.2 kg, a total of 10 birds and 5 eyes in each group.
Physiological saline was added to one eye of the wing, and 50 μg of the 0.1% urapidil eye drops obtained in Example 2 was weighed and instilled into the eye using a micropipette.
Kimwibe (Jujo Kimberly) who rolled the corneal surface for 0 minutes
(manufactured by J.D.) was stimulated 5 times and the number of reflexes was counted.
結果を第３表に示す。The results are shown in Table 3.
第 １ 表
［以下余白コ
第１〜３表から明らかなごと＜、ｏ、ｉ％ウラピジル点
眼薬は生理食塩水と同様の変化しか与えず、極めて副作
用が少ないことが分る。Table 1 [It is clear from Tables 1 to 3 in the margins below] It can be seen that o, i% urapidil eye drops produce only the same changes as physiological saline and have extremely few side effects.
実施例３ 以下の方法によって眼圧調整剤を調整した。Example 3 An intraocular pressure regulator was prepared by the following method.
（１）第４表に示す処方にしたがって２％、１％、０
、５９６ウラピジル点眼薬を調整した。(1) 2%, 1%, 0 according to the prescription shown in Table 4
, prepared 596 urapidil eye drops.
［以下余白］
ｆ２）第５表に示す処方にしたがって０．５％および２
％点眼薬を調整した。[Margin below] f2) 0.5% and 2% according to the prescription shown in Table 5.
% eye drops adjusted.
［以下余白］
（３）第６表に示す処方にしたがってｏ、ｏｏｏｉ％、
ｏ、ｏｏｉ％、０．０１％および０．１％ウラピジル点
眼薬を調整した。[Margin below] (3) o, oooi%, according to the prescription shown in Table 6.
o, ooi%, 0.01% and 0.1% urapidil eye drops were prepared.
［以下余白コ
［発明の効果］
本発明のウラピジルをを効成分とする眼圧調整剤は、す
ぐれた眼圧下降効果を奏する。しかも、刺激性が少なく
、瞳孔収縮作用、局所麻酔作用等の副作用がきわめて少
ないものである。[Margins below] [Effects of the Invention] The intraocular pressure regulating agent of the present invention containing urapidil as an active ingredient exhibits an excellent intraocular pressure lowering effect. Moreover, it is less irritating and has extremely few side effects such as pupil constriction and local anesthetic effects.
第１図は試験例１における２％、１％および０．５％ウ
ラピジル点眼薬ならびにコントロールを点眼したばあい
のそれぞれの眼圧の経時変化量を示すグラフであり、第
２図は試験例２における ０．１％、 ０．０１％、
０．００１％、０．０００１％ウラピジル点眼・薬およ
びコントロールを点眼したばあいのそれぞれの眼圧の経
時変化量を示すグラフである。FIG. 1 is a graph showing the amount of change in intraocular pressure over time when 2%, 1%, and 0.5% urapidil eye drops and the control were instilled in Test Example 1, and FIG. 0.1%, 0.01%,
It is a graph showing the amount of change in intraocular pressure over time when 0.001%, 0.0001% urapidil eye drops/drug and control were instilled.
Claims (1)
とを含有する請求項１記載の眼圧調整剤。[Claims] 1. An intraocular pressure regulating agent containing urapidil as an active ingredient. 2. The intraocular pressure regulating agent according to claim 1, containing urapidil and cyclodextrin or a derivative thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1084325A JPH02262518A (en) | 1989-04-03 | 1989-04-03 | Intraocular pressure-adjusting agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1084325A JPH02262518A (en) | 1989-04-03 | 1989-04-03 | Intraocular pressure-adjusting agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02262518A true JPH02262518A (en) | 1990-10-25 |
Family
ID=13827364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1084325A Pending JPH02262518A (en) | 1989-04-03 | 1989-04-03 | Intraocular pressure-adjusting agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02262518A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358935B1 (en) | 1998-09-02 | 2002-03-19 | Allergan Sales, Inc. | Preserved cyclodextrin-containing compositions |
| WO2001070230A3 (en) * | 2000-03-17 | 2002-04-25 | Alcon Universal Ltd | Compounds with 5-ht activity useful for controlling visual field loss |
| US7763619B2 (en) | 2000-03-17 | 2010-07-27 | Alcon, Inc. | Compounds with 5-HT1A activity useful for treating disorders of the outer retina |
-
1989
- 1989-04-03 JP JP1084325A patent/JPH02262518A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358935B1 (en) | 1998-09-02 | 2002-03-19 | Allergan Sales, Inc. | Preserved cyclodextrin-containing compositions |
| US6723353B2 (en) | 1998-09-02 | 2004-04-20 | Allergan, Inc. | Preserved cyclodextrin-containing compositions |
| WO2001070230A3 (en) * | 2000-03-17 | 2002-04-25 | Alcon Universal Ltd | Compounds with 5-ht activity useful for controlling visual field loss |
| WO2001070222A3 (en) * | 2000-03-17 | 2002-07-25 | Alcon Universal Ltd | Compounds with 5-ht1a activity useful for treating disorders of the outer retina |
| US7763619B2 (en) | 2000-03-17 | 2010-07-27 | Alcon, Inc. | Compounds with 5-HT1A activity useful for treating disorders of the outer retina |
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